CN1179155A - Heterocyclic compounds - Google Patents

Abstract

The present invention relates to N1-(Halogenocyclopropyl)-substituted pyridonecarboxylic acid derivatives represented by general formula (I), heterocyclic compounds useful as antibacterial agents, wherein X<1> represents halo or hydrogen; X<2> represents halo; R<1> represents hydrogen, hydroxy, thiol, halomethyl, amino, alkyl or alkoxy; R<2> represents a group of general formula (II) (wherein R<3> and R<4> represent each hydrogen or alkyl; and n represents an integer of 1 or 2); A represents nitrogen or a group of general formula (III), (wherein X<3> represents halo, cyano, amino, alkyl, halomethyl, alkoxy or halomethoxy); and R represents hydrogen, phenyl, acetoxymethyl, pivaloyloxymethyl, ethoxycarbonyl, choline, dimethylaminoethyl, 5-indanyl, phthalidinyl, 5-alkyl-2-oxo-1, 3-dioxol-4-ylmethyl, 3-acetoxy-2-oxobutyl, alkyl, alkoxymethyl or phenylalkyl.

Description

Heterogeneous ring compound

Technical field

The present invention relates to a kind of as medicine, veterinary drug, water industry medicine or the antimicrobial compounds of antibiotic antiseptic and antibacterials or the antibiotic preparation that contains them.

Background technology

Be disclosed in JP-A-64-56673 and JP-A-3-86875 (term used herein " JP-A " is meant " examining open Japanese patent application ") although contain 1-amino-3-azabicyclo [3.2.0] heptan-substituent Carbostyril derivative of 3-base, people but know nothing for containing by the condensing of described amino-replacement-bicyclic heterocycles deutero-substituting group and the Carbostyril derivative of the present invention that also contains the halogenated cyclopropyl group in the 1-position.

Recent years, it is found that synthetic quinolone antibacterial agent not only has anti-microbial activity, and have outstanding bio distribution for example oral absorption, organ distribution, homaluria rate etc., and many these compounds are now as being applied to clinical to the various effective chemotherapeutics that catch.But adopt in recent years, the bacterial strain that this medicine is had than Wheat Protein increases gradually clinically, and, (MRSA) has lower susceptibility to beta-lactam antibiotics as streptococcus aureus, the bacterial strain that synthetic quinolone antibacterial agent is had than Wheat Protein is also increasing, wherein some bacterial strain is not only to other drug, and synthetic quinolone antibacterial agent has also been produced resistance.Therefore, need to develop medicine clinically with higher effect.

Detailed Description Of The Invention

The inventor thinks; the structure that 7-and 1-position replace can influence the anti-microbial activity of synthetic quinolone antibacterial agent usually; effect and security; therefore; the inventor concentrates on studies; in the hope of obtaining broad spectrum of bacteria is comprised the compound that the drug-fast bacterial strain of quinolone is had higher anti-microbial activity; found that; on the 7-position, contain the substituent Carbostyril derivative of condensed-bicyclic heterogeneous ring compound deutero-by amino-replacement to Gram-positive and Gram-negative bacteria; particularly to the bacterium of anti-quinolone; comprise that MRSA has stronger anti-microbial activity; wherein the 1-position is by halogenated cyclopropyl; particularly the Carbostyril derivative of fluorine cyclopropyl replacement not only has anti-microbial activity, but also can obtain outstanding effect and security.

In Carbostyril derivative of the present invention, in other substituting groups, do not exist under the situation of heterogeneous phenomenon, only because of 1-position halo cyclopropane groups can produce a pair of enantiomorph, this is to be formed by the relation of the stereochemistry between pyridonecarboxylic acid group and the halogen atom on the described cyclopropane ring.When the isomer that is generated was racemoid, these derivatives were mixtures of the enantiomorph of useful as drug.

In addition, except the heterogeneous phenomenon of described halo cyclopropylene ring, when on other positions, when particularly also having heterogeneous phenomenon on the 7-bit substituent, this Carbostyril derivative is made of diastereomer, that is to say to have 4 or a plurality of steric isomer.Because non-enantiomer mixture is the mixture with compound of different physical propertys, therefore, be inconvenient as drug use with described mixture.

The present inventor concentrates on studies, and has obtained the Carbostyril derivative that is made of single stereoisomers, even under the situation of the Carbostyril derivative of the 1-that is made of diastereomer (1,2-is suitable-2-halogenated cyclopropyl)-replace.

As a result, the present inventor has successfully obtained each enantiomorph of the pure compound form of suitable-2-fluorine cyclopropylamine.The present inventor also by described pure suitable-compound form that the fluorine cyclopropylamine constitutes with individual isomer successfully obtained the enantiomorph of each described Carbostyril derivative that is formed by the fluorine cyclopropane ring.The present inventor has also successfully obtained to contain each isomer of the condensing of the amino-replacement-bicyclic heterocycles of unsymmetrical carbon and nitrogen heteroatom with the pure compound form.

Owing to successfully obtained all to can be used as the Carbostyril derivative of synthetic intermediate and condensing-bicyclic heterocycles of the amino-replacement that contains nitrogen heteroatom, made the synthetic single Carbostyril derivative of stereochemistry that constitutes by single diastereomer become possibility.

After this, the present inventor is on the basis of above-mentioned discovery, and finding to contain on the 7-position by the new Carbostyril derivative of the present invention that contains the halogenated cyclopropyl group on the condensing of amino-replacement-bicyclic heterocycles deutero-group and the 1-position is a kind ofly to have higher-security and the wide spectrum bacterial classification is comprised that the strains expressed to anti-quinolone goes out the compound of remarkable activity.

Therefore, the present invention relates to the N of a kind of following formula (I) expression ₁Pyridone carboxylic acid derivatives or its salt of-(halogenated cyclopropyl)-replacement: X wherein ¹Expression halogen atom or hydrogen atom;

X ²The expression halogen atom;

R ¹Expression hydrogen atom, hydroxyl, sulfydryl, halogenated methyl, amino, contain the alkyl of 1-6 carbon atom or contain the alkoxyl group of 1-6 carbon atom, wherein said amino can contain and is selected from formyl radical, contains the alkyl of 1-6 carbon atom and contains the substituting group of the acyl group of 2-5 carbon atom, condition is when described substituting group is alkyl, wherein alkyl can be same to each other or different to each other, and then described amino can be by dialkyl group-replacement;

R ²Expression is condensed-bicyclic heterocycle deutero-group by amino-replacement shown in the following formula (II): R wherein ³And R ⁴Represent hydrogen atom independently or contain the alkyl of 1-6 carbon atom and n is 1 or 2 integer; A represents the part-structure of nitrogen-atoms or following formula (III):

X wherein ³Expression hydrogen atom, halogen atom, cyano group, amino, contain 1-6 carbon atom

Alkyl, halogenated methyl, the alkoxyl group that contains 1-6 carbon atom, halogenated methoxy, its

Described in amino can containing be selected from formyl radical, contain the alkyl of 1-6 carbon atom and contain

The substituting group of the acyl group of 2-5 carbon atom, condition are when described substituting group is alkyl,

Wherein alkyl can be same to each other or different to each other, and then described amino can be by dialkyl group-get

Generation; Represent hydrogen atom, phenyl, acetoxy-methyl, oxy acid methyl neopentyl, ethoxycarbonyl, choline base, dimethyl aminoethyl, 5-indanyl, 2-stupid also [c] furanone alkynyl (phthalidynyl), 5-alkyl-2-oxo-1 with R, 3-dioxole-4-ylmethyl, 3-acetoxyl group-2-oxo butyl, contain 1-6 carbon atom alkyl, contain the alkoxy methyl of 2-7 carbon atom or the phenylalkyl that constitutes by alkylidene group that contains 1-6 carbon atom and phenyl.

The invention still further relates to above-claimed cpd or its salt, halogenated cyclopropyl is 1 described in its Chinese style (I), 2-is suitable-and the 2-halogenated cyclopropyl.

The invention still further relates to above-claimed cpd or its salt, R in its Chinese style (I) ²It is the pure substituting group of stereochemistry.

The invention still further relates to above-claimed cpd or its salt, halogenated cyclopropyl described in its Chinese style (I) is the pure substituting group of stereochemistry.

The invention still further relates to above-claimed cpd or its salt, wherein said halogenated cyclopropyl be (1R, 2S)-the 2-halogenated cyclopropyl.

The invention still further relates to above-claimed cpd or its salt, wherein X ²It is fluorine atom.

The invention still further relates to a kind of antibacterials, wherein said medicine contains above-mentioned formula (I) compound or its salt as activeconstituents.

Substituting group in formula of the present invention (I) compound is as mentioned below.

Work as X ¹, X ²And X ³When being halogen atom respectively, X ¹And X ²Most preferably be fluorine atom and X ³Preferably fluorine atom or chlorine atom.

R ¹Be hydrogen atom, hydroxyl, sulfydryl, halogenated methyl, amino, contain the alkyl of 1-6 carbon atom or contain the alkoxyl group of 1-6 carbon atom; wherein said amino can contain and is selected from formyl radical, contains the alkyl of 1-6 carbon atom and contains the substituting group of the acyl group of 2-5 carbon atom; condition is when described substituting group is alkyl; wherein alkyl can be same to each other or different to each other, and then described amino can be by dialkyl group-replacement.

For R ¹, described alkyl can be the straight or branched alkyl that contains 1-6 carbon atom, but preferably methyl, ethyl, n-propyl or sec.-propyl.

For the halogen atom in the described halogenated methyl, particularly preferably being fluorine atom and described atomicity can be 1-3.The preferred embodiment of halogenated methyl comprises methyl fluoride and difluoromethyl.

Work as R ¹When being amino, hydroxyl or sulfydryl, these groups can be by protecting group protection commonly used.

The example of this type of protecting group comprises for example tertbutyloxycarbonyl of carbalkoxy; 2; 2; 2-trichloro-ethoxycarbonyl etc.; aralkoxycarbonyl is carbobenzoxy-(Cbz) for example; to methoxyl group benzyloxy carbonyl; to nitro carbobenzoxy-(Cbz) etc.; acyl group is ethanoyl for example; the methoxyl group ethanoyl; trifluoroacetyl group; chloracetyl; valeryl; formyl radical; butyryl radicals etc.; alkyl or aralkyl be the tertiary butyl for example; benzyl; to nitrobenzyl; to methoxy-benzyl; trityl etc.; ether is methoxymethyl for example; the tert.-butoxy methyl; tetrahydropyrans; 2; 2; 2-trichlorine ethoxyl methyls etc. and silyl be trimethyl silyl for example; the sec.-propyl dimetylsilyl; t-butyldimethylsilyl; the tribenzyl silyl; t-butyldiphenylsilyl etc.

In these protecting groups, preferably can be with ether and silyl protecting group as hydroxyl and sulfydryl, and other protecting groups can be used as protecting group any in amino, hydroxyl and the sulfydryl.

X ³Be hydrogen atom, halogen atom, cyano group, amino, the alkyl that contains 1-6 carbon atom, halogenated methyl, the alkoxyl group that contains 1-6 carbon atom or halogenated methoxy; wherein said amino can contain and is selected from formyl radical, contains the alkyl of 1-6 carbon atom and contains the substituting group of the acyl group of 2-5 carbon atom; condition is when described substituting group is alkyl; wherein alkyl can be same to each other or different to each other, and then described amino can be by dialkyl group-replacement.

For X ³, described alkyl can be the straight or branched alkyl that contains 1-6 carbon atom, but preferably methyl, ethyl, n-propyl or sec.-propyl.

For the halogen atom in the described halogenated methyl, particularly preferably being fluorine atom and described atomicity can be 1-3.The preferred embodiment of halogenated methyl comprises methyl fluoride and difluoromethyl.

Described alkoxyl group can contain 1-6 carbon atom and methoxyl group preferably.

For the halogen atom in the described halogenated methyl, particularly preferably being fluorine atom and described atomicity can be 1-3.

When A is part-structure shown in the following formula (III), R ¹With X ³Between preferably combination be R ¹Be amino, hydrogen atom, hydroxyl or the alkyl that contains 1-6 carbon atom, and X ³Be the alkyl that contains 1-6 carbon atom, the alkoxyl group that contains 1-6 carbon atom, halogen atom, halogenated methoxy or hydrogen atom.

Preferred combination is R ¹Be amino, hydrogen atom, hydroxyl or methyl, and X ³Be methyl, methoxyl group, fluorine atom, chlorine atom, difluoro-methoxy or hydrogen atom.

Most preferred combination is R ¹Be amino, hydrogen atom, hydroxyl or methyl, and X ³It is methyl or methoxy.

For these R ¹And X ³Group, preferably X ¹And X ²It is fluorine atom.

R ²Be the group shown in the following formula (II):

It is derived from condensing-bicyclic heterocycles of the amino-replacement shown in the following formula: Although (illustrated by this situation that hydrogen replaces with the nitrogen-atoms that is 5-unit ring here, in fact its can by other substituting groups for example nitrogen atom protecting group replace).This group contains amino substituting group on bridge carbon atom, as if therefore, this group has little alicyclic cyclammonium structure, thereby the inventor thinks that this structure plays an important role in the outstanding characteristic that The compounds of this invention showed.

Term used herein " condense-bicyclic heterocycles " be meant contain by will condense-the one-tenth ring carbon atom of dicyclic hydrocarbon compound is by the heteroatoms compound of the structure that forms of replacing such as nitrogen-atoms for example.

In the following formula, R ³And R ⁴Represent hydrogen atom independently or contain the alkyl of 1-6 carbon atom and n is 1 or 2 integer.Described alkyl can be the straight or branched alkyl that contains 1-6 carbon atom, and methyl preferably.

In addition, R ³And R ⁴Can contain the methene chain of 2-6 carbon atom and contain and R in conjunction with formation ³And R ⁴The ring structure of the nitrogen-atoms of bonding.

At R ³And R ⁴Preferably combination in, R ³And R ⁴In one be hydrogen atom, and another is the alkyl that contains 1-6 carbon atom.

In preferred combination, R ³And R ⁴In one be hydrogen atom, and another is methyl or ethyl.

In addition, n is 1 or 2 integer.

The present inventor finds that following groups also is preferred R ²Substituting group.

Known, contain the substituent Carbostyril derivative of 3-aminomethyl pyrrolidine gram-positive microorganism is had stronger anti-microbial activity.For example, at pharmaceutical chemistry magazine (Journal of MedicinalChemistry) vol.29, p.445,7-(3-aminomethyl pyrrolidine base) Carbostyril carboxylic acid derivatives is disclosed in (1986), and at pharmaceutical chemistry magazine vol.37, p.733 7-[3-(1-amino-1-methylethyl) pyrrolidyl is disclosed in (1994)] Carbostyril carboxylic acid derivatives.

In addition, although have the Carbostyril derivative of 3-aminoalkyl group pyrrolidyl on the 7-position gram-feminine gender and gram-positive bacteria are shown stronger anti-microbial activity, but the chemical compound lot in them not only acts on bacterium, but also act on eukaryotic cell, at this moment because they have lower selective toxicity, make to be difficult to them as medicine or veterinary drug.

The inventor concentrates on studies to the Carbostyril derivative that has 3-aminoalkyl group pyrrolidyl on the 7-position, found that, when all being the non-hydrogen atom substituting group on quinolone skeleton 5-and the 8-position, can obtain to have higher anti-microbial activity, outstanding security and the toxic Carbostyril derivative of highly selective.

Just, the pyrrolidyl group that contains aminoalkyl groups shown in the described preferably following formula of 3-aminoalkyl group pyrrolidyl (IV) on the 3-position: It is derived from the aminoalkyl group of 3-shown in following formula pyrrolidine compound:

Although (illustrated by this situation that hydrogen replaces with the tetramethyleneimine nitrogen-atoms here, in fact its can by other substituting groups for example nitrogen atom protecting group replace).

In the following formula, R ⁵And R ⁶Represent hydrogen atom independently or contain the alkyl of 1-3 carbon atom.Described alkyl can be the straight or branched alkyl, and preferably methyl or ethyl.

In addition, R ⁵And R ⁶Can contain the methene chain of 2-6 carbon atom and contain and R in conjunction with formation ⁵And R ⁶The ring structure of the nitrogen-atoms of bonding.

R ⁷Expression contains the alkyl and the R of 1-6 carbon atom ⁸Expression hydrogen atom or contain the alkyl of 1-6 carbon atom.

At R ⁵And R ⁶In the preferably combination, R ⁵And R ⁶One of be hydrogen atom, and another is the alkyl that contains 1-3 carbon atom.

Preferred combination is R ⁵And R ⁶One of be hydrogen atom, and another is methyl or ethyl.

The pyrrolidin derivatives that has aminoalkyl group on the 3-position can prepare according to method described in for example JP-A-63-166876 or the JP-A-3-72476.

In addition, the inventor finds that also the substituent Carbostyril derivative of saturated nitrogen heterocyclic ring that contains amino group of naphthene base-replacement is to gram-positive bacteria, and particularly MRSA shows strong anti-microbial activity.

Just, the wherein R that contains structure shown in the following formula V ²It is the substituent situation of saturated nitrogen heterocyclic ring.

In this formula, R ⁹Be hydrogen atom or the alkyl that contains 1-6 carbon atom.Described alkyl can be the straight or branched alkyl that contains 1-6 carbon atom, and preferably methyl, ethyl, n-propyl or sec.-propyl.

R ¹⁰Be hydrogen atom, contain 1-6 carbon atom alkyl, contain the alkyl that contains hydroxyl of 1-6 carbon atom or contain the alkyl that contains halogen atom of 1-6 carbon atom.

Described alkyl can be the straight or branched alkyl that contains 1-6 carbon atom, and preferably methyl, ethyl, n-propyl or sec.-propyl.

For the hydroxyalkyl that contains 1-6 carbon atom, preferably 2-hydroxyethyl or 3-hydroxypropyl.

For the halogen atom in the alkyl that contains halogen atom that contains 1-6 carbon atom, particularly preferably be 1-3 fluorine atom.The alkyl that replaces for the halogen atom that contains 1-6 carbon atom particularly preferably is 2-fluoro ethyl, 2,2-two fluoro ethyls or 2,2,2-trifluoroethyl.

In addition, R ⁹And R ¹⁰Can contain the methene chain of 2-6 carbon atom and contain and R in conjunction with formation ⁹And R ¹⁰The ring structure of the nitrogen-atoms of bonding.

At R ⁹And R ¹⁰In the preferably combination, R ⁹And R ¹⁰One of be hydrogen atom, and another is the alkyl that contains 1-6 carbon atom, perhaps R ⁹Be hydrogen atom and R ¹⁰It is the hydroxyalkyl that contains 1-6 carbon atom.

Preferred combination is R ⁵And R ⁶One of be hydrogen atom, and another is methyl or ethyl, perhaps R ⁹Be hydrogen atom and R ¹⁰It is the 2-hydroxyethyl.

And p is the integer of 1-3, preferably 2 and q be the integer of 1-3, preferably 1 or 2.

At described quinolone compounds parent nucleus 7-position and R ²Bonding most preferably is to form R ²On the nitrogen-atoms of ring structure, also can be R ²On carbon atom on carry out.

Work as R ²On when having steric isomerism, the quinolone parent nucleus compound can be directly and R ²The formula R in substituting group source ²The reaction of the stereoisomer mixture of compound shown in the-H, because on the 1-position 1,2-is suitable-existence of 2-halogenated cyclopropyl, then the gained Carbostyril derivative becomes the mixture of diastereomer, works as R ²On when having steric isomerism, comparatively ideal is only to make described R ²A kind of isomer in the-H compound and the reaction of described quinolone parent nucleus compound.

Work as R ²Be introduced on the 7-position of described quinolone and described R ²When containing amino group in the-H compound, described amino group can react with the compound that can be transformed into the GPF (General Protection False base.

The example of this type of protecting group comprises for example tertbutyloxycarbonyl of carbalkoxy; 2; 2; 2-trichloro-ethoxycarbonyl etc.; aromatic alkoxy carbonyl is carbobenzoxy-(Cbz) for example; to methoxyl group benzyloxy carbonyl; to nitro carbobenzoxy-(Cbz) etc.; acyl group is ethanoyl for example; the methoxyl group ethanoyl; trifluoroacetyl group; the chloro ethanoyl; valeryl; formyl radical; benzoyl etc.; alkyl or aralkyl be the tertiary butyl for example; benzyl; to nitrobenzyl; to methoxy-benzyl; trityl etc.; alkyl sulphonyl or halogenated alkyl sulfonyl be methylsulfonyl for example; trifyl etc., and aryl sulfonyl benzenesulfonyl for example; tosyl group etc.

In addition, N ₁The above halogenated cyclopropyl group of-position is as mentioned below.

Example as substituent halogen atom comprises fluorine atom and chlorine atom, wherein particularly preferably is fluorine atom.

Consider the stereochemistry environment of this group, it is desirable to especially that with respect to described cyclopropane ring, described halogen atom and pyridonecarboxylic acid group are cisoid conformations.

Described enantiomorph isomer be only thus the 1-position suitable-2-halogenated cyclopropyl group forms, with

R on other locational substituent steric isomerisms, particularly 7-position ²Irrelevant, we find that these isomer have stronger anti-microbial activity and higher security.

When The compounds of this invention (I) has when wherein having the diastereomer structure and this type of The compounds of this invention being administered to humans and animals, comparatively ideally be the compound that use is made of pure diastereomer.Described term " is made of pure diastereomer " and not only is meant the situation that does not have other diastereomers fully, and is meant the situation of chemical pure degree.In other words be exactly, under this degree, can contain other diastereomers, but it does not constitute influence to physical constant and biological activity.

In addition, term " stereochemistry is pure " is meant when because the existence of its unsymmetrical carbon, and when compound contained various isomeric forms, described compound only was made of a kind of in these isomeric forms.At this moment, term " pure " also can be considered to above-mentioned identical implication.

Pyridone carboxylic acid derivatives of the present invention can use with the form of its free form or acid salt or its carboxyl salt.The example of described acid salt comprises inorganic acid salt for example hydrochloride, vitriol, nitrate, hydrobromate, hydriodate, phosphoric acid salt etc., and organic acid salt is acetate, mesylate, benzene sulfonate, tosylate, Citrate trianion, maleate, fumarate, lactic acid salt etc. for example.

Described carboxyl salt can be any in the inorganic and organic salt, an alkali metal salts such as lithium salts, sodium salt, sylvite for example, alkaline earth salts such as magnesium salts, calcium salt, ammonium salt, triethylamine salt, N-methyl glutaminate, three-(methylol) aminomethane salt etc.

In addition, the free form of described pyridone carboxylic acid derivatives, acid salt and carboxyl salt also can exist with the form of hydrate.

And wherein carboxylic moiety is that the Carbostyril derivative of ester can be used as synthetic intermediate and prodrug.For example, alkyl ester, benzyl ester, alkoxy alkyl, phenylalkyl ester and phenylester can be used as synthetic intermediate.

The example that can be used as the ester of prodrug is the ester that is easy to be hydrolyzed into the free carboxy acid in vivo, for example acetoxy-methyl ester, oxy acid methyl neopentyl ester, ethoxycarbonyl ester, cholinesterase, dimethylaminoethyl ester, 5-2,3-indanyl ester, phthalidyl ester and oxoalkyl group ester be 5-alkyl-2-oxo-1 for example, 3-dioxole-4-ylmethyl ester, 3-acetoxyl group-2-oxo butyl ester etc.

Compound of the present invention shown in the formula (I) can in all sorts of ways and make.A kind of preferred examples is that described compound can be by following method preparation, even formula R ²-H compound (R wherein ²Except described amino group can be by the protecting group Rx of the nitrogen-atoms protection, as definition in the above-mentioned formula (I)) or its acid salt and formula (VI) shown in compound (quinolone parent nucleus compound) react:

Wherein X is the substituting group that can be used as leavings group; for example benzenesulfonyl, tosyl group etc. of fluorine atom, chlorine atom, the alkyl sulphonyl that contains 1-3 carbon atom or aryl sulfonyl for example, the group of R or formula (VII) expression identical with defined R in the formula (I): R wherein ¹¹And R ¹²Be respectively fluorine atom or lower alkyl carbonyl oxygen base, and X ¹, X ², R ¹Define suc as formula (I) is middle with A.

Described nitrogen atom protecting group Rx can be that this area any group commonly used and the example of this type of protecting group comprise for example tertbutyloxycarbonyl of carbalkoxy; 2; 2; 2-trichloro-ethoxycarbonyl etc.; aralkoxycarbonyl is carbobenzoxy-(Cbz) for example; to methoxyl group benzyloxy carbonyl; to nitro carbobenzoxy-(Cbz) etc.; acyl group is ethanoyl for example; the methoxyl group ethanoyl; trifluoroacetyl group; the chloro ethanoyl; valeryl; formyl radical; benzoyl etc.; alkyl or aralkyl be the tertiary butyl for example; benzyl; to nitrobenzyl; to methoxy-benzyl; trityl etc.; alkyl sulphonyl or halogenated alkyl sulfonyl be methylsulfonyl for example; trifyl etc., and aryl sulfonyl benzenesulfonyl for example; tosyl group etc.

When R is during by aralkyl deutero-carboxylic acid; described aralkyl contains the alkyl of 1-6 carbon atom, the alkoxy methyl of a 2-7 carbon atom or the group that is made of alkylidene group that contains 1-6 carbon atom and phenyl; compound shown in the interesting formula (I) can be under acidity or alkaline condition that the carboxyl ester hydrolysis is used always; obtain by the reaction that converts corresponding carboxylic acid to; and; if desired; this moment, other substituting groups can be protected, and then remove protecting group under corresponding suitable condition.

When the R in formula (VI) compound is the group of above-mentioned formula (VII) expression, by at first using described compound R ²-H carries out substitution reaction, handles with acidity or basic cpd then, can be converted into corresponding carboxylic acid.

Formula (VI) compound and R ²The substitution reaction that-H compound carries out can or do not have to carry out in the presence of the solvent.When using solvent, it can be to be the inert solvent under the reaction conditions.The example of suitable solvent comprises methyl-sulphoxide, pyridine, acetonitrile, ethanol, chloroform, dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, tetrahydrofuran (THF), water, 3-methoxybutanol and composition thereof.

Described reaction normally in room temperature to 200 ℃, is preferably carried out under 25-150 ℃.Reaction times is 30 minutes to 48 hours, and described reaction was finished in 2 hours at 30 minutes usually.

More advantageously, the described acid acceptor that is reflected at carries out under existing, and described acid acceptor comprises for example for example triethylamine, pyridine etc. of basic metal or alkaline earth metal carbonate or supercarbonate and organo-alkali compound of mineral alkali.

The synthetic example of the condensing of amino-replacement-bicyclic heterocycles has hereinafter been described.For example, can make the 1-t-butoxycarbonyl amino that constitutes by the pure isomer of stereochemistry-3-[(1S)-styroyl by following method]-3-azabicyclo [3.1.0] hexane.

That is, at first make solvent and make (S)-(-)-styroyl amine and Racemic glycidol reaction with ethanol, then with acrylonitrile reactor, obtain N-(2-cyano ethyl)-N-[(1S)-styroyl]-3-amino-1, the 2-propylene glycol.Make the reaction of this compound and triphenylphosphine and carbon tetrabromide, obtain N-(2-cyano ethyl)-N-[(1S)-styroyl]-3-amino-1,2-two bromo propane.In the presence of highly basic, make this compound react, obtain 1-cyano group-3-[(1S)-styroyl]-3-azabicyclo [3.1.0] hexane.Because this compound is containing styroyl and contain unsymmetrical carbon on the 1-position on the 3-position, what therefore obtain is non-enantiomer mixture.These isomer can be separated from each other by silica gel column chromatography or high performance liquid chromatography.Use ordinary method, each isomer and alkali reaction that order so obtains obtain 3-[(1S)-styroyl]-3-azabicyclo [3.1.0] hexane-1-carboxylic acid.When this compound carried out Ku Ertisi (Curtius) reaction in the presence of the trimethyl carbinol, it can be transformed into protected 3-[(1S immediately)-styroyl]-3-azabicyclo [3.1.0] hexane-1-carboxylic acid.When using diphenyl phosphoryl azide, this reaction can be carried out at an easy rate, but to synthesizing at this of described intermediate azide not playing any qualification effect, and can use any conventional synthetic method.When removing described styroyl group thus in the compound by catalytic hydrogenation, then can obtain 1-t-butoxycarbonyl amino-3-azabicyclo [3.1.0] hexane that constitutes by pure optical isomer with ordinary method.

For example, can obtain 1-tertbutyloxycarbonyl-3-azabicyclo [3.2.0] heptane of constituting by the stereochemistry individual isomer by following method.

That is, make 1-bromo cyclobutene carboxylic acid, ethyl ester and alkali reaction, obtain 1-cyclobutene carboxylic acid.By using alkali, obtain 1-cyclobutene carboxylic acid, ethyl ester with this compound and iodoethane reaction.Use acid as catalyst, with this compound and n-butoxy methyl trimethoxy base silyl methyl [(S)-styroyl] amine reaction, obtain 3-[(S)-styroyl]-3-azabicyclo [3.2.0] heptane-1-carboxylic acid, ethyl ester, in this reaction, can be with trifluoroacetic acid for example as described acid.Owing to contain styroyl and on the 1-position, contain unsymmetrical carbon on the 3-position in this compound, therefore obtain non-enantiomer mixture.These isomer can be separated from one another by silica gel column chromatography or high performance liquid chromatography.Each isomer and benzyl chloroformate reaction with so obtaining obtain 3-carbobenzoxy-(Cbz)-3-azabicyclo [3.2.0] heptane-1-carboxylic acid, ethyl ester.Use ordinary method, this compound is carried out ester hydrolysis reaction, obtain 3-carbobenzoxy-(Cbz)-3-azabicyclo [3.2.0] heptane-1-carboxylic acid.When this compound carried out Curtius reaction in the presence of the trimethyl carbinol, it can be transformed into protected 1-tertbutyloxycarbonyl-3-carbobenzoxy-(Cbz)-3-azabicyclo [3.2.0] heptane immediately.When using diphenyl phosphoryl azide, this reaction can be carried out at an easy rate, but to synthesizing at this of described intermediate azide not playing any qualification effect, and can use any conventional synthetic method.When removing described carbobenzoxy-(Cbz) group thus in the compound by catalytic hydrogenation, then can obtain 1-tertbutyloxycarbonyl-3-azabicyclo [3.2.0] heptane that constitutes by pure optical isomer with ordinary method.

Hereinafter described the synthetic example of the saturated nitrogen-containing heterocycle compound of amino cycloalkyl-replacement, it is essential for the saturated nitrogen heterocyclic ring group of introducing described amino cycloalkyl-replacement.In reaction formula or explanation what follows, Me is that methyl, Et are that ethyl, Ph are that phenyl, Z are that carbobenzoxy-(Cbz), Boc are that tertbutyloxycarbonyl, TFA are that trifluoroacetic acid and Ts are p-toluenesulfonyl.In some cases, arrow represents that described reactions steps has multiple choices.

1. the preparation of (3R)-3-(the amino cyclopropyl of 1-) tetramethyleneimine:

To be disclosed in (the 3R)-ethyl 1-[(R in the United States Patent (USP) 621,101)-styroyl] tetramethyleneimine-3-acetic ester and benzyl chloroformate reaction, obtain (3R)-ethyl 1-carbobenzoxy-(Cbz)-tetramethyleneimine-3-acetic ester.

Then, this compound is at first reacted with highly basic, with the reaction of chlorocarbonic acid ethyl ester, obtain 1-carbobenzoxy-(Cbz)-3-(R)-pyrrolidyl malonic ester then.With this compound and alkali reaction, obtain 1-carbobenzoxy-(Cbz)-3-(R)-pyrrolidyl propanedioic acid hydrogen ethyl ester.

Then, with this compound and Eschenmoser reactant salt, obtain 2-(1-carbobenzoxy-(Cbz)-3-(R)-pyrrolidyl) ethyl propenoate.Make catalyzer with acid chloride, make this compound and diazomethane reaction, obtain 1-(1-carbobenzoxy-(Cbz)-3-(R)-pyrrolidyl) cyclopropane carboxylic acid acetoacetic ester.

Then, use ordinary method,, this compound is transformed into 1-(1-carbobenzoxy-(Cbz)-3-(R)-pyrrolidyl) cyclopropane-carboxylic acid by being hydrolyzed with alkali.

When in the presence of the trimethyl carbinol, when this compound was carried out Curtius reaction, it can be transformed into protected (3R)-1-carbobenzoxy-(Cbz)-3-(1-t-butoxycarbonyl amino cyclopropyl) tetramethyleneimine immediately.When using diphenyl phosphoryl azide, this reaction can be carried out at an easy rate, but to synthesizing at this of described intermediate azide not playing any qualification effect, and can use any conventional synthetic method.

When with conventional catalytic hydrogenation method or similar approach, when removing Z in gained (3R)-1-carbobenzoxy-(Cbz)-3--(1-t-butoxycarbonyl amino cyclopropyl) tetramethyleneimine, then can obtain (3R)-3-(1-t-butoxycarbonyl amino cyclopropyl) tetramethyleneimine.

In addition, when replacing (3R)-ethyl [1-(R)-styroyl] tetramethyleneimine-3-acetic ester with (3S)-ethyl [1-(S)-styroyl] tetramethyleneimine-3-acetic ester, can obtain (3S)-3-(the amino cyclopropyl of 1-) pyrrolidin derivatives.

And, also can obtain (3R)-1-carbobenzoxy-(Cbz)-(1-ethoxycarbonyl cyclopropyl) tetramethyleneimine with following method.

2. the synthetic method of another kind of (3R)-3-(the amino cyclopropyl of 1-) tetramethyleneimine:

With methyl aceto acetate and 1, the reaction of 2-two bromo ethane obtains 1-ethanoyl cyclopropane carboxylic acid acetoacetic ester.Then, make the reaction of 1-ethanoyl cyclopropane carboxylic acid acetoacetic ester and zinc powder and bromoethyl acetate, obtain 1-ethoxycarbonyl-beta-hydroxy-Beta-methyl-cyclopropane carboxylic acid acetoacetic ester.

Then, make solvent with pyridine, with this compound and thionyl chloride reaction, obtain 1-ethoxycarbonyl-β-chloro-β methyl cyclopropane propionic ester, then with alkali reaction, obtain (E)-ethyl 3-(1-ethoxycarbonyl cyclopropyl)-2-butylene acid esters, the example of used organic bases comprises pyridine, 2,6-lutidine and similar aromatic heterocycle compounds, and 1,8-diazabicyclo [5.4.0] 11-7-alkene, 1,5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-organic basess such as 5-alkene.

With (E)-ethyl 3-(1-ethoxycarbonyl cyclopropyl)-2-butylene acid esters and the N-bromosuccinimide reaction that so obtains, obtain (E)-ethyl 4-bromo-3-(1-ethoxycarbonyl cyclopropyl)-2-butylene acid esters, make then its with (S)-reaction of phenyl-ethylamine, obtain 4-(1-ethoxycarbonyl cyclopropyl)-1-[(S)-1-styroyl]-the 3-pyrrolidin-2-one.This compound is carried out conventional catalytic hydrogenation, obtains 4-(1-ethoxycarbonyl cyclopropyl)-1-[(S)-styroyl]-2-Pyrrolidone.Owing to there is (S)-styroyl group on the 1-position, therefore, this compound is a non-enantiomer mixture.This mixture can be separated with fractional recrystallization or silica gel column chromatography.

With so isolated (4R)-4-(1-ethoxycarbonyl cyclopropyl)-1-[(S)-styroyl]-2-Pyrrolidone and Lawesson reagent react, obtain (4S)-4-(1-ethoxycarbonyl cyclopropyl)-1-[(S)-styroyl]-2-tetramethyleneimine thioketones.This reaction also can be carried out with thiophosphoric anhydride.

With (4S)-4-(1-ethoxycarbonyl cyclopropyl)-the 1-[(S)-styroyl that so obtains]-2-tetramethyleneimine thioketones and Raney nickel reaction, with the benzyl chloroformate reaction, obtain (3R)-1-carbobenzoxy-(Cbz)-(1-ethoxycarbonyl cyclopropyl) tetramethyleneimine then.

After this,, obtain (3R)-3-(the amino cyclopropyl of 1-) tetramethyleneimine through above-mentioned reaction.

Can synthesize with following method and to obtain (3R)-3-(1-alkylamino cyclopropyl) tetramethyleneimine or (3R)-1-[1-(N-tertbutyloxycarbonyl-N-(2-hydroxyethyl) amino) cyclopropyl] tetramethyleneimine.

3. the preparation of (3R)-3-(the amino cyclopropyl that 1-replaces) tetramethyleneimine:

In order to obtain (3R)-3-(1-methylamino-cyclopropyl) tetramethyleneimine, at first in N, in the dinethylformamide, with (3R)-1-carbobenzoxy-(Cbz)-3-(1-t-butoxycarbonyl amino cyclopropyl) tetramethyleneimine and methyl iodide and silver suboxide reaction, obtain the amino cyclopropyl of (3R)-1-carbobenzoxy-(Cbz)-3-[1-(N-tertbutyloxycarbonyl-N-methyl)] tetramethyleneimine.

When replacing methyl iodide, can obtain the amino cyclopropyl of (3R)-1-carbobenzoxy-(Cbz)-3-[1-(N-tertbutyloxycarbonyl-N-ethyl) with iodoethane] tetramethyleneimine.

After this,, remove Z in the compound thus, obtain (3R)-3-(1-alkylamino cyclopropyl) tetramethyleneimine through conventional catalytic hydrogenation.

In order to obtain (3R)-1-[1-(N-tertbutyloxycarbonyl-N-(2-hydroxyethyl) amino) cyclopropyl] tetramethyleneimine; at first under acidic conditions; make its reaction with trifluoroacetic acid, hydrochloric acid etc.; by removing Boc in (3R)-1-carbobenzoxy-(Cbz)-3-(1-t-butoxycarbonyl amino cyclopropyl) tetramethyleneimine; then triethylamine or similarly acid remove in the presence of the agent product and benzyloxy excess acetyl chloride, obtain the amino cyclopropyl of (3R)-3-{1-(benzyloxy ethanoyl)]-1-carbobenzoxy-(Cbz) tetramethyleneimine.

By with borine-tetrahydrofuran (THF) mixture with the reduction of this compound, to addition Boc wherein, can obtain the amino cyclopropyl of (3R)-1-carbobenzoxy-(Cbz)-3-[1-(N-2-benzyloxy ethyl-N-tertbutyloxycarbonyl) then] tetramethyleneimine.

After this,, remove described benzyl and Z thus in the compound, obtain (3R)-1-[1-(N-tertbutyloxycarbonyl-N-(2-hydroxyethyl) amino) cyclopropyl through conventional catalytic hydrogenation] tetramethyleneimine.

For example, can make 3-(1-t-butoxycarbonyl amino cyclobutyl) tetramethyleneimine with following method.

The preparation of (4.3-1-t-butoxycarbonyl amino cyclobutyl) tetramethyleneimine:

Make solvent with the trimethyl carbinol, with 1,1-cyclobutane dicarboxylic acid hydrogen ethyl ester and diphenylphosphoric acid trinitride and triethylamine or similar acid remove agent one and react, and obtain 1-t-butoxycarbonyl amino cyclobutane carboxylate.

Under alkaline condition,, obtain 1-t-butoxycarbonyl amino cyclobutane-carboxylic acid with the ester hydrolysis of this compound.Make this compound and 1,1 '-reaction such as carbonyl dimidazoles, dicyclohexyl carbodiimide, chlorine carbonic ether, obtain active ester or acid anhydride mixture, the magnesium salts with propanedioic acid hydrogen ethyl ester reacts then, obtains 1-t-butoxycarbonyl amino-β-oxo tetramethylene ethyl propionate.

With this compound sodium borohydride reduction, obtain 1-t-butoxycarbonyl amino-beta-hydroxy tetramethylene ethyl propionate.

Remove agent with triethylamine, pyridine or similar alkali do acid, by with itself and methylsulfonyl chloride or Tosyl chloride reaction, this compound is transformed into sulphonate, then with gained compound and pyridine, 2,6-lutidine or similar aromatic heterocycle compounds or 1,8-diazabicyclo [5.4.0] 11-7-alkene, 1,5-diazabicyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene or similarly organic bases reaction obtain 1-t-butoxycarbonyl amino tetramethylene ethyl propenoate.

By described alcohol being transformed into carboxylic acid halides,, also can synthesizing and obtain this compound then with product and above-mentioned alkali reaction with thionyl chloride or thionyl bromide.

In the presence of alkali,, obtain 3-(1-t-butoxycarbonyl amino cyclobutyl)-4-nitro ethyl butyrate with this compound and Nitromethane 99Min. reaction.The example of used alkali comprises 1,1,3 in this reaction, 3-tetramethyl--guanidine, 1,8-diazabicyclo [5.4.0] 11-7-alkene and similar organic bases.

This reaction can be carried out as solvent with solvent or with Nitromethane 99Min..The example of solvent for use is to be those solvents of inert under described reaction conditions in this reaction, for example benzene, toluene and similarly aromatic substance, chloroform, methylene dichloride and the similarly compound that replaces of chlorine or ether, tetrahydrofuran (THF) and similarly ether compound.

When the 3-of acquisition like this (1-t-butoxycarbonyl amino cyclobutyl)-when 4-nitro ethyl butyrate carried out conventional catalytic hydrogenation, after nitro was reduced into amino, cyclization immediately obtained 4-(1-t-butoxycarbonyl amino cyclobutyl)-2-Pyrrolidone.

When the 4-amino-3-that has not cyclization (1-t-butoxycarbonyl amino cyclobutyl) butyric ester,,, can be converted into 4-(1-t-butoxycarbonyl amino cyclobutyl)-2-Pyrrolidone by being heated being with or without in the presence of benzene, toluene or the similar solvent.

In this ring-closure reaction, can use sodium ethylate, butanols potassium or similar alkali.

Then, with 4-(1-t-butoxycarbonyl amino cyclobutyl)-2-Pyrrolidone and bromotoluene that is used as alkali or benzyl chloride reaction, obtain 1-benzyl-4-(1-t-butoxycarbonyl amino cyclobutyl)-2-Pyrrolidone.

Under acidic conditions, handle this compound to remove Boc, obtain 4-(the amino cyclobutyl of 1-)-1-benzyl-2-Pyrrolidone subsequently.This reaction can be carried out with any Boc of removing method commonly used.

In following reaction, can with the acid salt form for example trifluoroacetate or by reaction back with ordinary method with the free form that its neutralization obtains, use 4-(the amino cyclobutyl of 1-)-1-benzyl-2-Pyrrolidone trifluoroacetate.

Remove in the presence of the agent at pyridine or similar acid; with 4-(the amino cyclobutyl of 1-)-1-benzyl-2-Pyrrolidone trifluoroacetate and D-(R)-p-toluenesulfonyl-prolyl chlorine reaction; obtain 1-benzyl-4-[1-[N '-p-toluenesulfonyl-2-(R)-tetramethyleneimine carbonyl] amino cyclobutyl]-2-Pyrrolidone, then it is separated into 2 steric isomers.

The separation of described isomer can be carried out with silica gel column chromatography or high performance liquid chromatography.

With each the isomer acid hydrolysis that so obtains, obtain optically active 1-benzyl-4-(the amino cyclobutyl of 1-)-2-Pyrrolidone.With each optically active isomer and lithium aluminium hydride reaction, obtain 1-benzyl-3-(the amino cyclobutyl of 1-) tetramethyleneimine, subsequently itself and two dimethyl dicarbonate butyl esters are reacted, obtain 1-benzyl-3-(1-t-butoxycarbonyl amino cyclobutyl) tetramethyleneimine.

When this compound being carried out catalytic hydrogenation, obtain optically active 3-(1-t-butoxycarbonyl amino cyclobutyl) tetramethyleneimine with ordinary method.

For example, can make 3-(1-t-butoxycarbonyl amino cyclopropyl) azetidine with following method.

The preparation of (5.3-1-t-butoxycarbonyl amino cyclopropyl) azetidine:

Remove agent with acid,, obtain 1-diphenyl-methyl-3-(tolysulfonyl oxygen base) azetidine 1-diphenyl-methyl-3-hydroxy azetidine and Tosyl chloride reaction.In the presence of alkali,, obtain (1-benzhydryl-3-aza ring butane group) diethyl malonate with this compound and diethyl malonate reaction.

With this compound and benzyl chloroformate reaction, obtain (1-carbobenzoxy-(Cbz)-3-azetidinyl) diethyl malonate,, obtain (1-carbobenzoxy-(Cbz)-3-azetidinyl) propanedioic acid hydrogen ethyl ester then with its hydrolysis of carrying out the part ester.

With this compound and Eschenmoser reactant salt, obtain 2-(1-carbobenzoxy-(Cbz)-3-azetidinyl) ethyl propenoate.Utilize alkali,, obtain 1-(1-carbobenzoxy-(Cbz)-3-azetidinyl) cyclopropane-carboxylic acid, ethyl ester this compound and the reaction of trimethylammonium sulfoxonium iodide.

With this compound hydrolysis, obtain 1-(1-carbobenzoxy-(Cbz)-3-azetidinyl) cyclopropane-carboxylic acid, in the presence of alkali, make solvent then with the trimethyl carbinol, itself and diphenylphosphoric acid trinitride are reacted, obtain 1-carbobenzoxy-(Cbz)-3-(1-t-butoxycarbonyl amino cyclopropyl) azetidine.This compound is carried out catalytic hydrogenation with ordinary method, obtain 3-(1-t-butoxycarbonyl amino cyclopropyl) azetidine.

Formula (IV) or the substituent quinolone compounds of (V) representing that contains can make with the identical method of substituent quinolone compounds that contains of preparation formula (II) expression.

In addition, according to for example method described in the JP-A-2-231475, by optical activity suitable-2-fluorine cyclopropylamine derivative also can synthesize and obtain formula (VIII) compound that is made of individual isomer.

As a kind of compound in the formula (VIII), 6,7,8-three fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-5-hydroxyl-4-Oxoquinoline-3-carboxylic acid ester can make by following method.

With 2,3,4; 5,6-penta fluoro benzene formyl radical ethyl acetate and N, the reaction of dinethylformamide dimethyl-acetal; remove the agent existence down in triethylamine or similar acid then, with (1R, 2S)-reaction of 2-fluorine cyclopropylamine; obtain 5 subsequently; 6,7,8-tetrafluoro-1-[(1R; 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester.

In the presence of alkali, with this compound and benzylalcohol reaction, obtain 5-benzyloxy-6,7,8-three fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester.This reaction can be carried out according to any method well known in the art, and the example of used alkali comprises sodium hydride, salt of wormwood, sodium hydroxide and potassium hydroxide in the reaction.

Under acidic conditions, handle this compound, can obtain 6,7,8-three fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-5-hydroxyl-4-Oxoquinoline-3-carboxylic acid ester.

Utilize above-mentioned same procedure, with containing 2,4 of low alkyl group on the 3-position, 5-three fluoro-6-nitrobenzoic acids are made raw material, can make wherein R ¹Be amino and X ³Be a kind of formula (VIII) compound of low alkyl group, wherein said raw material can be by will containing 2,4 of low alkyl group with ordinary method on the 3-position, and the 5-trifluoro-benzoic acid carries out nitrification and makes.

Although 3-methyl-2,4, the 5-trifluoro-benzoic acid can be according to the preparation of method described in JP-A-61-205240 or the JP-A-3-95176, and it also can obtain with following method is more easily synthetic.

That is, for example, utilize alkali, with 3,4,5,6-ptfe phthalate diester and diester malonate reaction obtain 4-diethoxy carbonyl methyl-3,5,6-trifluoro-phthalic acid diethyl ester.

Operable alkali can be mineral alkali in this reaction, it also can be organic bases, and the example of described mineral alkali comprises alkali metal hydroxide, carbonate, supercarbonate etc., for example lithium hydroxide, sodium hydroxide, potassium hydroxide, Quilonum Retard, yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus etc.In this reaction, also can use for example quaternary ammonium salt etc. of phase-transfer catalyst.

The example of organic bases comprises trialkylamine for example triethylamine, tripropylamine, tributylamine, N, N-diisopropyl ethyl amine etc., dialkyl aniline is Diethyl Aniline, xylidine etc. for example, and saturated or aromatic heterocycle compounds for example N-methylmorpholine, pyridine, N, N-Dimethylamino pyridine etc.

When using solvent, it can be to be the inert solvent under the reaction conditions.The example of suitable solvent comprises methyl-sulphoxide, pyridine, acetonitrile, ethanol, chloroform, dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, tetrahydrofuran (THF), benzene, toluene, water and composition thereof.

Described reaction can preferably be carried out under 25-100 ℃ at 0-150 ℃ usually.

Then, under acidity or alkaline condition, with 4-diethoxy carbonyl methyl-3,5, the hydrolysis of 6-trifluoro-phthalic acid diethyl ester obtains 4-carboxymethyl-3,5, the 6-trifluoro-phthalic acid.

The example of used acid comprises the vitriol oil and concentrated hydrochloric acid in this reaction.The example of described alkali comprises mineral alkali for example alkali metal hydroxide, carbonate, supercarbonate etc., comprises lithium hydroxide, sodium hydroxide, potassium hydroxide, Quilonum Retard, yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus etc.

In the presence of alkali, with the 4-carboxymethyl-3,5 that so obtains, the 6-trifluoro-phthalic acid heats in methyl-sulphoxide, obtains 3-methyl-2,4, the 5-trifluoro-benzoic acid.

The example of used organic bases comprises trialkylamine for example triethylamine, tripropylamine, tributylamine, N in this reaction, N-diisopropyl ethyl amine etc., dialkyl aniline is Diethyl Aniline, xylidine etc. for example, and saturated or aromatic heterocycle compounds for example N-Methyl pyrrolidone, pyridine, N, N-Dimethylamino pyridine etc.

Described reaction is by can preferably carrying out under 100-150 ℃ at 100-200 ℃.Described reaction can be carried out 1-96 hour, but generally can finish in 5-48 hour.

When with 3,4,5,6-tetrafluoro phthalonitrile replaces 3,4,5, and when 6-ptfe phthalate diester was made raw material, this preparation process same methods was carried out.In addition, replace diester malonate with propane dinitrile, and can prepare 3-alkyl-2,4 with alkyl diester malonate and alkyl propane dinitrile, 5-three fluoro-6-nitrobenzoic acids wherein contain the alkyl group of non-methyl.

Because The compounds of this invention shows stronger anti-microbial activity, so it can be used as medicine that is suitable for people, animal and fish use or the sanitas that is used as agrochemical substances and feed.

When compound of the present invention was used as the medicine that is suitable for people's use, for the adult, its dosage can be at 50mg-1g every day, in the preferred 100mg-300mg scope.

When being applicable to animal, its dosage will be according to kind and the size of medication purpose (treatment or prevention), every kind of animal being treated, kind of the pathogenic bacterium that infect and gradient of infection and decide, but normally at per kilogram the weight of animals 1-200mg every day, preferably in the 5-100mg scope.

Described per daily dose can be once-a-day or be divided into 2-4 time every day.If desired, described per daily dose can surpass above-mentioned scope.

Because The compounds of this invention has activity to causing the various broad-spectrum micro-organisms that catch, so it can cure, prevents or alleviate the disease that these pathogenic microorganisms cause.

The bacterium of The compounds of this invention sensitivity and the example of bacterium sample microorganism are comprised Staphylococcus, streptococcus pyogenes, Hemolytic streptococcus, enterococcus spp, Peptostreptococcus, gonococcus, bacillus coli, citrobacter, Shigella, Friedlander bacillus, enterobacter, serratia, proteus, Pseudomonas aeruginosa, hemophilus influenzae, acinetobacter, campylobacter, chlamydia trachomatis etc.

The example of the caused disease of these pathogenic microorganisms comprises folliculitis, furuncle, carbuncle, erysipelas, phlegmon, lymphangitis, the pyogenic infection of the pad of a finger, subcutaneous abscess, spiradenitis, the Cuo blister, the infectivity sebaceous cyst, perirectal abscess, mazoitis, the surface secondary infection for example damages, burn, wound etc., pharyngolaryngitis, acute bronchitis, tonsillitis, chronic bronchitis, bronchiectasis, the dispersivity panbronchiolitis, the secondary infection of chronic respiratory disease, pneumonia, pyelonephritis, urocystitis, prostatitis, epididymitis, gonococcal urethritis, non gonococcal urethritis, cholecystitis, cholangitis, bacillary dysentery, enteritis, adnexitis, intra-uterine infection, bartholinitis, blepharitis, sty, dacryocystitis, meibomitis, keratohelcosis, otitis media, sinusitis, periodontitis, the corona inflammation, ganathitis, peritonitis, endocarditis, sepsis, meningitis, dermatitis etc.

The compounds of this invention is also effective to the various microorganisms that cause the zoogenetic infection disease, for example belongs to following microorganism: Colibacter, salmonella, pasteurella, hemophilus, bordetella genus, Staphylococcus, mycoplasma etc.The illustrative example of this type of disease comprises for bird, comprise colibacillosis, white diarrhea, chicken paratyphoid, fowl cholera, the infective rhinitis, staphylococcal infections, mycoplasmas infection etc., comprise colibacillosis for pig, salmonellosis, pasteurellosis, the influenzae disease, the atopic rhinitis, exudative epidermitis, mycoplasmas infection etc., comprise colibacillosis for ox, salmonellosis, the hemorrhagic sepsis, mycoplasmas infects, pleuropneumonia, bovine mastitis etc., comprise intestinal sepsis for dog, Salmonella infection, the hemorrhagic sepsis, pyometra, urocystitis etc., and comprise wet pleurisy for cat, urocystitis, chronic rhinitis, hemophilus infection, kitten diarrhoea, mycoplasmas infection etc.

The antiseptic-germicide that contains The compounds of this invention can make by the preparation method of the optimal dose utilization of selecting to adapt with every kind of application process various pharmaceutical preparations commonly used.The example that contains as the antiseptic-germicide formulation of the The compounds of this invention of activeconstituents comprises oral preparations for example tablet, pulvis, capsule, solution, syrup, elixir, oil or water suspending agent etc.

When using as injection, described preparation can contain stablizer, sanitas and solubilizing agent.As required, the solution that can contain auxiliary substance can be loaded in the container and by lyophilize or additive method make use before dissolved solid preparation once more.In addition, in the container single dose or multiple doses can be housed.

Antiseptic-germicide of the present invention also can be prepared into the formulation example that is suitable for external application such as solution, suspension agent, emulsion, ointment, gel, emulsion, lotion, sprays etc.

Solid preparation can contain pharmaceutically acceptable additive and active compound and can be by the additive that will be selected from for example weighting agent, swelling agent, tackiness agent, disintegrating agent, solubilizing agent, wetting agent, lubricant etc. arbitrarily mixed.

Liquid preparation comprises solution, suspension, emulsion of additives such as can containing suspension agent, emulsifying agent etc.

When The compounds of this invention is administered to animal, it can for example be undertaken by following method, it is directly Orally administered or to add in the feed back to Orally administered to be about to described compound, additive method also has, described compound is made solution, directly Orally administered then or add the Orally administered or injection in back in drinking-water or the feed to.

When using The compounds of this invention to animal, available this area ordinary method at random is prepared into pulvis, fine powder (subtilae), soluble powder, syrup or injection.

The ingredients embodiment of pharmaceutical preparation is as mentioned below.Example of formulations 1 (capsule)

Inventive embodiments 2 compound 100.0mg

W-Gum 23.0mg

CMC calcium 22.5mg

Walocel MT 20.000PV 3.0mg

Magnesium Stearate 1.5mg

Amount to 150.0mg example of formulations 2 (solution)

Inventive embodiments 2 compound 1-10g

Acetate or sodium hydroxide 0.5-2g

Ethyl p-hydroxybenzoate 0.1g

Purified water 88.9-98.4g

Amount to 100g example of formulations 3 (being suitable for the pulvis of mixed feeding)

Inventive embodiments 2 compound 1-10g

W-Gum 98.5-89.5g

Soft silicic anhydride 0.5g

Amount to 100g

Optimum implementation of the present invention

Following inventive embodiments and reference example have further been illustrated the present invention, but do not play any qualification effect.For the anti-microbial activity of interested optically active compound, test according to ordinary method described in the Japan Societyof Chemotherapy, the result sees Table 1 with MIC (μ g/ml) expression.Reference example A-1:N-(2-cyano ethyl)-N-[(1S)-styroyl]-3-amino-1, the 2-propylene glycol

Under ice-cooled condition, (37g, (75ml in ethanol 0.58mol) (500ml) solution, and stirred mixture 20 minutes under room temperature, reflux is 62 hours then 0.5mol) to join (S)-(-) styroyl amine with Racemic glycidol.After wherein adding vinyl cyanide (40ml),, concentrate then reaction mixture refluxed heating 45 hours.After this, with gained resistates silica gel column chromatography purifying, and, obtain the described title compound of 121g (84%) with 5% methyl alcohol-chloroform wash-out. ¹H-NMR(CDCl ₃)δ：

1.41-1.48(3H，m)，2.39-2.50(2H，m)，2.60-3.25

(4H，m)，3.41-3.46(IH，m)，3.68-3.78(2H，m)，3.93

-4.02 (1H, m), 7.27-7.40 (5H, m). reference example A-2:N-(2-cyano ethyl)-N-[(1S)-styroyl]-3-amino-1,2-two bromo propane

To N-(2-cyano ethyl)-N-[(1S)-styroyl]-3-amino-1, the 2-propylene glycol (24.8g, add in benzene 0.1mol) (400ml) solution triphenylphosphine (57.71g, 0.22mol) and carbon tetrabromide (73g, 0.22mol).Stir down, with gained mixture heating up to 90 ℃, tell supernatant liquor after, with solvent evaporation, gained resistates silica gel column chromatography purifying, and, obtain the described title compound of 38g (100%) with normal hexane-ethyl acetate (4: 1) wash-out. ¹H-NMR(CDCl ₃)δ：

1.43-1.46(3H，m)，2.35-2.44(2H，m)，2.82-2.96

(3H，m)，3.14-3.27(1H，m)，3.67-4.15(4H，m)，7.27

-7.40 (5H, m). reference example A-31-cyano group-3-[(1S)-styroyl]-3-azabicyclo [3.1.0] hexane

The ice bath cooling down, to N-(2-cyano ethyl)-N-[(1S)-styroyl]-3-amino-1,2-two bromo propane (37.4g, 0.1mol) toluene (700ml) solution in drip 1M (two trimethyl silyl) ammonification sodium (220ml, 0.22mol) tetrahydrofuran solution, stirred subsequently 20 minutes.After reaction is finished, in described reaction soln, drip saturated aqueous ammonium chloride (100ml), be warmed to room temperature subsequently.Tell organic layer, with saturated brine washing, dried over sodium sulfate then.After steaming desolventizes, with described resistates silica gel column chromatography purifying, and with normal hexane-ethyl acetate (9: 1) wash-out, obtain the low polarity cut (cut 1) of the described title compound of 7.93g (37%), obtain the high polarity cut (cut 2) of the described title compound of 7.85g (36%) then.Cut 1; ¹H-NMR (CDCl ₃) δ:

1.09(1H，dd，J＝4.5，8.3Hz)，1.29(3H，d，J＝6.4

Hz)，1.57(1H，t，J＝4.5Hz)，1.95-1.99(1H，m)，

2.27(1H，dd，J＝3.9，9.8Hz)，2.61(1H，d，J＝8.8

Hz)，2.68(1H，d，J＝9.8Hz)，3.33-3.38(2H，m)，

7.21-7.31 (5H, m). cut 2; ¹H-NMR (CDCl ₃) δ:

1.09(1H，dd，J＝4.9，8.3Hz)，1.29(3H，d，J＝6.4

Hz)，1.55-1.58(1H，m)，2.04-2.09(1H，m)，2.35

(1H，d，J＝8.8Hz)，2.53(1H，dd，J＝3.9，9.3Hz)，

2.86(1H，d，J＝9.3Hz)，3.18(1H，d，J＝9.3Hz)，

3.32-3.37 (1H, m), 7.21-7.32 (5H, m). reference example A-4:3-[(1S)-styroyl]-3-azabicyclo [3.1.0] hexane-1-carboxylic acid (cut 1)

To 1-cyano group-3-[(1S)-styroyl]-(cut 1,5.6g add 2N aqueous sodium hydroxide solution (50ml) to 3-azabicyclo [3.1.0] hexane in methyl alcohol 26.4mmol) (500ml) solution, reflux is 30 hours subsequently.Steam except that behind the methyl alcohol, the gained resistates transfers to pH3 with chloroform (30ml * 2) washing with concentrated hydrochloric acid, uses propyl carbinol (80ml * 3) extraction then.With the extraction liquid dried over sodium sulfate, steaming desolventizes then, obtains the crude product of the described title compound of 6.11g (100%).It is directly used in following reaction.Reference example A-5:3-[(1S)-styroyl]-3-azabicyclo [3.1.0] hexane-1-carboxylic acid

Cut 2 is also carried out same reaction.Reference example A-6:1-t-butoxycarbonyl amino-3-[(1S)-styroyl]-3-azabicyclo [310] hexane (cut 1)

To 3-[(1S)-styroyl]-3-azabicyclo [3.1.0] hexane-1-carboxylic acid (cut 1,6.11g, add in trimethyl carbinol 266.4mmol) (200ml) solution diphenylphosphoric acid trinitride (9.99g, 34.3mmol) and triethylamine (4.23g, 36.9mmol), reflux is 4 hours subsequently.After the reaction soln cooling, steaming desolventizes and the gained resistates is mixed with the 200ml ethyl acetate, with saturated brine (50ml * 2) washing, uses dried over sodium sulfate then.After steaming desolventizes,, and, obtain the described title compound of 3.19g (40%) with normal hexane-ethyl acetate (4: 1) wash-out with gained resistates silica gel column chromatography purifying. ¹H-NMR(CDCl ₃)δ：

0.67-0.71(1H，m)，1.25-1.31(4H，m)，1.45(9H，s)，

1.60(1H，brs.)，2.30-2.38(1H，m)，2.51-2.58(2H，

m)，3.20-3.35(2H，m)，4.96(1H，brs.)，7.20-7.29

(5H, m). reference example A-7:1-t-butoxycarbonyl amino-3-[(1S)-styroyl]-3-azabicyclo [3.1.0] hexane (cut 2) ¹H-NMR (CDCl ₃) δ:

0.69-0.71(1H，m)，1.25(3H，d，J＝6.4Hz)，1.39

(9H，s)，1.50-1.72(2H，m)，2.29(1H，d，J＝8.3Hz)，

2.58-2.82(2H，m)，3.08-3.15(1H，m)，3.30-3.38

(1H, m), 4.82 (1H, brs.), 7.19-7.37 (5H, m). reference example A-8:1-t-butoxycarbonyl amino-3-azabicyclo [3.1.0] hexane (cut 1)

To 1-t-butoxycarbonyl amino-3-[(1S)-styroyl]-3-azabicyclo [3.1.0] hexane (cut 1,3.1g, 10.26mmol) ethanol (50ml) solution in add 10% palladium/carbon (3g), subsequently at tungsten lamp under warm and 4 normal atmosphere, catalytic hydrogenation 3 hours.Behind the filtration catalizer, steaming desolventizes, and obtains the described title compound of 2.04g (100%). ¹H-NMR(CDCl ₃)δ：

0.85-1.14(2H，m)，1.44(9H，s)，1.44-1.7?0(1H，m)，

2.95-3.34 (4H, m), 5.0 8 (1H, brs.). reference example B-1:1-cyclobutene carboxylic acid

After reflux stopped together with 85% potassium hydroxide solution and 125ml toluene, the speed that refluxes with maintenance dripped 10g (48.31mmol) 1-bromo cyclobutene carboxylic acid, ethyl ester in described solution.After dripping, with gained mixture reflux 1 hour again.After being chilled to room temperature, to wherein adding entry and telling formed water layer.It is used hexane wash, use the 1N hcl acidifying, use extracted with diethyl ether then.Organic layer water and saturated brine washing are also used anhydrous sodium sulfate drying.Steaming desolventizes, and obtains the crude product of the described title compound of 4.1047g (41.88mmol, 86.7%).Reference example B-2:1-cyclobutene carboxylic acid, ethyl ester

In the 60ml dimethyl formamide solution of the 1-cyclobutene carboxylic acid of 3.2425g (33.09mmol), add 12ml (150mmol) iodoethane and 5.53g (40mmol) salt of wormwood, under room temperature, stirred 20 hours subsequently.With in the reaction soln impouring water and use extracted with diethyl ether.Organic layer water and saturated brine washing are also used anhydrous sodium sulfate drying.Steaming desolventizes, and obtains the described title compound of 4.5267g with the form of mixtures that contains iodoethane and ether. ¹H-NMR(400?MHz，CDCl ₃)δ：

1.29(3H，t，J＝7.5Hz)，2.47(1H，dt，J＝1.0，3.0

Hz)，2.73(1H，t，J＝3.0Hz)，4.19(2H，q，J＝7.5

Hz), 6.77 (1H, t, J=1.0Hz). reference example B-3:3-[(S)-styroyl]-3-azabicyclo [3.2.0] heptane-1-carboxylic acid, ethyl ester

The ice bath cooling down, 0.116ml (1.5mmol) trifluoroacetic acid is added drop-wise in methylene dichloride (100ml) solution of the above-mentioned 1-cyclobutene carboxylic acid, ethyl ester of 4.5267g (33.09mmol) and iodoethane and ether mixture and 14.65g (50mmol) azomethane (azomethinylide), under room temperature, stirred 64 hours subsequently.With in the reaction soln impouring saturated sodium bicarbonate aqueous solution and use chloroform extraction.Anhydrous sodium sulfate drying is used in organic layer water and saturated brine washing then.After steaming desolventizes, with the gained resistates through silica gel column chromatography (normal hexane: ethyl acetate=10: 1) purifying, obtain the described title compound of 4.1832g (14.58mmol, the 44.1% 2 step reactions that begin by reference example B-2) non-enantiomer mixture form.This mixture is separated through high performance liquid chromatography, obtain 1.9203g (6.69mmol, the 20.2% 2 step reactions that begin by reference example B-2) low polarity product (cut 1) and 990.5mg (3.45mmol, 10.4% 2 steps that begun by reference example B-2 reacted) high polarity product (cut 2).Low polarity product (cut 1) ¹H-NMR (400MHz, CDCl ₃) δ:

1.21(3H，t，J＝7.0Hz)，1.40(3H，d，J＝6.5Hz)，

1.77-1.84(1H，m)，1.97-2.05(1H，m)，2.11-2.20

(1H，m)，2.29(1H，dd，J＝6.0，9.0Hz)，2.38(1H，dt，

J＝6.5，11.0Hz)，2.69(1H，d，J＝9.0Hz)，2.96(1H，

dt，J＝5.0，9.5Hz)，3.07(1H，d，J＝9.0Hz)，3.29

(1H，q，J＝6.5Hz)，4.10(2H，q，J＝7.0Hz)，7.21-

7.33 (3H, m), 7.39-7.41 (2H, m). high polarity product (cut 2) ¹H-NMR (400 MHz, CDCl ₃) δ:

1.28(3H，t，J＝7.5Hz)，1.40(3H，d，J＝6.5Hz)，

1.68-1.72(1H，m)，2.02-2.18(3H，m)，2.41(1H，d，

J＝9.0Hz)，2.45-2.50(1H，m)，2.55(1H，d，J＝9.0

Hz)，2.82-2.87(1H，m)，3.19(1H，d，J＝9.0Hz)，

3.29(1H，q，J＝6.5Hz)，4.10(2H，q，J＝7.5Hz)，

7.21-7.41 (5H, m). reference example B-4:3-carbobenzoxy-(Cbz)-3-azabicyclo [3.2.0] heptane-1-carboxylic acid, ethyl ester (cut 1)

Ice-cooled down, to 980mg (3.41mmol) 3-[(S)-styroyl]-drip 0.714ml (5.0mmol) benzyl chloroformate in methylene dichloride (20ml) solution of 3-azabicyclo [3.2.0] heptane-1-carboxylic acid, ethyl ester, under room temperature, stirred 40 hours subsequently.After steaming desolventized, (normal hexane: ethyl acetate=4: 1) purifying obtained the described title compound of 921.5mg (2.91mmol, 85.3%) through column chromatography with the gained resistates.Reference example B-5:3-carbobenzoxy-(Cbz)-3-azabicyclo [3.2.0] heptane-1-carboxylic acid, ethyl ester (cut 2)

The ice bath cooling down, to 863.8mg (3.01mmol) 3-[(S)-styroyl]-drip 0.642ml (4.5mmol) benzyl chloroformate in methylene dichloride (15ml) solution of 3-azabicyclo [3.2.0] heptane-1-carboxylic acid, ethyl ester, under room temperature, stirred 45 hours subsequently.After steaming desolventized, (normal hexane: ethyl acetate=4: 1) purifying obtained the described title compound of 829mg (2.62mmol, 87.0%) through column chromatography with the gained resistates. ¹H-NMR(400?MHz，CDCl ₃)δ：

1.27(3H，t，J＝7.0Hz)，1.72(1H，br)，1.97(1H，br)，

2.22(1H，br)，2.56(1H，dt，J＝8.0，11.5Hz)，3.10

(1H，dd，J＝6.5，14.5Hz)，3.38-3.42(1H，m)，3.66-

3.84(3H，m)，4.18(2H，q，J＝7.0Hz)，5.18(2H，s)，

7.27-7.40 (5H, m). reference example B-6:3-carbobenzoxy-(Cbz)-3-azabicyclo [3.2.0] heptane-1-carboxylic acid (cut 1)

The ice bath cooling adds the 6ml1N aqueous sodium hydroxide solution down in ethanol (10ml) solution of 920mg (2.90mmol) 1-ethoxycarbonyl-3-carbobenzoxy-(Cbz)-3-azabicyclo [3.2.0] heptane, stirred 2 hours under room temperature subsequently.With in the 1N aqueous hydrochloric acid and after, steam to remove ethanol.With gained resistates and 1N combined and use chloroform extraction.Organic layer is with the saturated brine washing and use anhydrous sodium sulfate drying.Steaming desolventizes, and obtains the described title compound crude product of 847.2mg (quantitatively).Reference example B-7:3-carbobenzoxy-(Cbz)-3-azabicyclo [3.2.0] heptane-1-carboxylic acid (cut 2)

The ice bath cooling adds the 5ml1N aqueous sodium hydroxide solution down in ethanol (10ml) solution of 825mg (2.60mmol) 1-ethoxycarbonyl-3-carbobenzoxy-(Cbz)-3-azabicyclo [3.2.0] heptane, stirred 2 hours under room temperature subsequently.With in the 1N aqueous hydrochloric acid and after, steam to remove ethanol.With gained resistates and 1N combined and use chloroform extraction.Organic layer is with the saturated brine washing and use anhydrous sodium sulfate drying.Steaming desolventizes, and obtains the described title compound crude product of 776.6mg (quantitatively). ¹H-NMR(400MHz，CDCl ₃)δ：

1.75(1H，br)，2.00(1H，br)，2.25(1H，br)，2.59-

2.66(1H，m)，3.14-3.19(1H，m)，3.39-3.44(1H，m)，

3.66-3.81(2H，m)，3.84-3.91(1H，m)，5.18(2H，s)，

7.29-7.39 (5H, m). reference example B-8:1-tertbutyloxycarbonyl-3-carbobenzoxy-(Cbz)-3-azabicyclo [3.2.0] heptane (cut 1)

In the trimethyl carbinol (15ml) solution of 3-carbobenzoxy-(Cbz)-3-azabicyclo [3.2.0] heptane-1-carboxylic acid (2.90mmol), add 0.53ml (3.8mmol) triethylamine and 0.819ml (3.8mmol) diphenyl phosphoryl azide, stirred 9 hours down in 70 ℃ subsequently.After being cooled to room temperature, with in the described reaction soln impouring saturated sodium bicarbonate and use ethyl acetate extraction.Organic layer water and saturated brine washing are also used anhydrous sodium sulfate drying.After steaming desolventized, (normal hexane: ethyl acetate=4: 1) purifying obtained the described title compound of 817.8mg (2.27mmol, the 78.3% 2 step reactions that begun by reference example B-2) through silica gel column chromatography with the gained resistates.Reference example B-9:1-tertbutyloxycarbonyl-3-carbobenzoxy-(Cbz)-3-azabicyclo [3.2.0] heptane (cut 2)

In the trimethyl carbinol (15ml) solution of 3-carbobenzoxy-(Cbz)-3-azabicyclo [3.2.0] heptane-1-carboxylic acid (2.60mmol), add 0.474ml (3.4mmol) triethylamine and 0.733ml (3.4mmol) diphenyl phosphoryl azide, stirred 9 hours down in 70 ℃ subsequently.After being cooled to room temperature, with in the described reaction soln impouring saturated sodium bicarbonate and use ethyl acetate extraction.Organic layer water and saturated brine washing are also used anhydrous sodium sulfate drying.After steaming desolventized, (normal hexane: ethyl acetate=4: 1) purifying obtained the described title compound of 642.2mg (1.78mmol, the 68.4% 2 step reactions that begun by reference example B-7) through silica gel column chromatography with the gained resistates. ¹H-NMR(400MHz，CDCl ₃)δ：

1.43(9H，s)，2.18(3H，br)，2.85(1H，br)，3.45-3.65

(3H，m)，3.87(1H，br)，4.80(1H，br)，5.16(2H，s)，

7.310-7.37 (5H, m). reference example B-10:1-tertbutyloxycarbonyl-3-azabicyclo [3.2.0] heptane (cut 1)

In methyl alcohol (20ml) solution of 368mg (1.02mmol) 1-tertbutyloxycarbonyl-3-carbobenzoxy-(Cbz)-3-azabicyclo [3.2.0] heptane, add 400mg 20% palladium hydroxide-carbon, under nitrogen atmosphere, carry out vigorous stirring subsequently.After diatomite filtration is removed insolubles, gained filtrate is concentrated, obtain the described title compound crude product of 274.6mg.Reference example B-11:1-tertbutyloxycarbonyl-3-azabicyclo [3.2.0] heptane (cut 2)

In methyl alcohol (20ml) solution of 360mg (1.02mmol) l-tertbutyloxycarbonyl-3-carbobenzoxy-(Cbz)-3-azabicyclo [3.2.0] heptane, add 400mg 20% palladium hydroxide-carbon, under nitrogen atmosphere, carry out vigorous stirring subsequently.After diatomite filtration is removed insolubles, gained filtrate is concentrated, obtain the described title compound crude product of 243.8mg. ¹H-NMR(400MHz，CD ₃OD)δ：

1.54(9H，s)，1.76-1.83(1H，m)，2.31-2.45(3H，m)，

3.07-3.22(1H，m)，3.40-3.48(1H，m)，3.51-3.67

(2H, m), 3.68-3.71 (1H, m). inventive embodiments 1:5-amino-7-(1-amino-3-azabicyclo [3.1.0] hexane-3-yl)-6,8-two fluoro-1-[(2S)-fluoro-(1R)-cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid (cut 1)

To 5-amino-6,7,8-three fluoro-1-[(2S)-and fluoro-(1R)-cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid (316mg, add 1-tertbutyloxycarbonyl-3-azabicyclo [3.1.0] hexane (cut 1) (396mg in acetonitrile 1mmol) (15ml) solution, 2mmol) and triethylamine (5ml), reflux is 2 hours subsequently.After steaming desolventizes, the gained resistates is mixed with chloroform (20ml), with 10% citric acid (10ml * 2) washing, use dried over sodium sulfate then, steaming subsequently desolventizes.Gained resistates and mixed being incorporated under the room temperature of concentrated hydrochloric acid (5ml) were stirred 5 minutes.Reaction soln with chloroform (5ml * 2) washing, is transferred to pH7.3 with 20% aqueous sodium hydroxide solution, use chloroform (30ml * 3) extraction then.After dried over sodium sulfate, steaming desolventizes, and obtains the described title compound crude product of 190mg (48%).After this, with described crude product recrystallization in chloroform-methanol-ethanol, obtain the described title compound of 111mg. ¹H-NMR(0.1N-NaOD)δ：

0.61-0.64(1H，m)，0.80-0.83(1H，m)，1.21-1.83

(3H，m)，3.23-3.79(5H，m)，4.87-4.98(0.5H，m)，

8.21(1H，s).

Ultimate analysis C ₁₈H ₁₈F ₃N ₄O ₃0.25H ₂O:

Calculated value: C, 54.07; H, 4.66; N, 14.01

Measured value: C, 53.98; H, 4.54; N, 13.82 fusing points (℃): 191-203 (decomposition) [α] _D+ 72.37 ° (T=22.4 ℃, c=0.665,0.1N-NaOH) inventive embodiments 2:7-(1-amino-3-azabicyclo [3.1.0] hexane-3-yl)-6-fluoro-1-[(2S)-fluoro-(1R)-cyclopropyl]-the 8-methyl isophthalic acid, 4-dihydro-4-Oxoquinoline-3-carboxylic acid (cut 1)

To 6,7-two fluoro-1-[(2S)-fluoro-(1R)-cyclopropyl]-the 8-methyl isophthalic acid, 4-dihydro-4-Oxoquinoline-3-carboxylic acid BF2 inner complex (345mg, add 1-tertbutyloxycarbonyl-3-azabicyclo [3.1.0] hexane (cut 1) (298mg in tetramethylene sulfone 1mmol) (4ml) solution, 1.5mmol) and triethylamine (0.2ml), under room temperature, stirred 200 hours subsequently.Steam except that behind the triethylamine, gained resistates and mixed being incorporated under the room temperature of water (10ml) were stirred 30 minutes.The crystallization that is settled out is washed with water, filter to collect also and be dissolved in ethanol: in water=4: 1 (50ml) mixed solvent, and gained solution mixed also reflux 3 hours with triethylamine (5ml).After steaming desolventizes, the gained resistates is mixed with chloroform (50ml), with 10% citric acid (20ml * 2) washing, use dried over mgso then, steaming subsequently desolventizes.Gained resistates and mixed being incorporated under the room temperature of concentrated hydrochloric acid (5ml) were stirred 5 minutes.Reaction soln with chloroform (5ml * 2) washing, is transferred to pH7.3 with 20% aqueous sodium hydroxide solution, use chloroform (30ml * 3) extraction then.After dried over sodium sulfate, steaming desolventizes.The gained resistates is carried out separation and purification through preparation TLC (use chloroform: methyl alcohol: water=low layer launched in 7: 3: 1), obtain the described title compound crude product of 35mg.After this, with described crude product recrystallization in chloroform-ethanol, obtain the described title compound of 18mg. ¹H-NMR(0.1N-NaOD)δ：

0.78-0.83(2H，m)，1.12-1.21(1H，m)，1.38-1.39

(1H，m)，1.51-1.62(1H，m)，2.36(3H，s)，3.03(1H，

d，J＝9.3Hz)，3.31(1H，d，J＝9.3Hz)，3.56(1H，d，

J＝9.3Hz)，3.72-3.74(1H，m)，3.99-4.04(1H，m)，

5.00-5.08(0.5H，m)，7.60(1H，d，J＝13.67Hz)，8.44

(1H，d，J＝2.4Hz).

Ultimate analysis C ₁₉H ₁₉F ₂N ₃O ₃0.75H ₂O:

Calculated value: C, 58.68; H, 5.31; N, 10.81

Measured value: C, 59.01; H, 5.15; N, 10.65 fusing points (℃): 189-210 (decomposition) inventive embodiments 3:7-(1-amino-3-azabicyclo [3.1.0] hexane-3-yl)-6-fluoro-1-[(2S)-fluoro-(1R)-cyclopropyl]-the 8-methyl isophthalic acid, 4-dihydro-4-Oxoquinoline-3-carboxylic acid (cut 2)

With cut 2, also can synthesize described title compound according to same procedure described in the inventive embodiments 2. ¹H-NMR(0.1N-NaOD)δ：

0.75-0.83(2H，m)，1.13-1.17(1H，m)，1.39-1.41

(1H，m)，1.55-1.61(1H，m)，2.39(3H，s)，3.26(1H，

d，J＝9.3Hz)，3.35(1H，d，J＝9.3Hz)，3.47-3.49

(1H，m)，3.55-3.60(1H，m)，3.98-4.04(1H，m)，5.01

-5.08(0.5H，m)，7.62(1H，d，J＝13.67Hz)，8.45(1H，

d，J＝1.9Hz).

Ultimate analysis C ₁₉H ₁₉F ₂N ₃O ₃0.25H ₂O:

Calculated value: C, 60.07; H, 5.17; N, 11.06

Measured value: C, 59.87; H, 5.33; N, 10.46 fusing points (℃): 200-217 (decomposition) inventive embodiments 4:7-(1-amino-3-azabicyclo [3.1.0] hexane-3-yl)-6-fluoro-1-[(2S)-fluoro-(1R)-cyclopropyl]-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid (cut 1)

To 6,7-two fluoro-1-[(2S)-fluoro-(1R)-cyclopropyl]-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid BF2 inner complex (217mg, 0.6mmol) methyl-sulphoxide (2.5ml) solution in add 1-tertbutyloxycarbonyl-3-azabicyclo [3.1.0] hexane (cut 1) (170mg, 0.86mmol) and triethylamine (0.2ml), under room temperature, stirred 150 hours subsequently.Steam except that behind the triethylamine, gained resistates and mixed being incorporated under the room temperature of water (10ml) were stirred 30 minutes.The crystallization that is settled out is washed with water, filter to collect also and be dissolved in ethanol: in water=4: 1 (20ml) mixed solution, and gained solution mixed also reflux 2 hours with triethylamine (3ml).After steaming desolventizes, the gained resistates is mixed with chloroform (30ml), with 10% citric acid (10ml * 2) washing, use dried over mgso then, steaming subsequently desolventizes.Gained resistates and mixed being incorporated under the room temperature of concentrated hydrochloric acid (5ml) were stirred 5 minutes.Reaction soln with chloroform (5ml * 2) washing, is transferred to pH7.3 with 20% aqueous sodium hydroxide solution, use chloroform (30ml * 3) extraction then.After dried over sodium sulfate, steaming desolventizes, and obtains the described title compound crude product of 175mg (74%).After this, with described crude product recrystallization in chloroform-alcohol-ether, obtain the described title compound of 80mg. ¹H-NMR(0.1N-NaOD)δ：

0.67-0.69(1H，m)，0.82-0.85(1H，m)，1.40-1.66

(3H，m)，3.42-3.61(4H，m)，3.54(3H，s)，3.98-4.03

(1H，m)，4.98-5.05(0.5H，m)，7.64(1H，d，J＝13.67

Hz)，8.47(1H，s).

Ultimate analysis C ₁₉H ₁₉F ₂N ₃O ₄0.25H ₂O:

Calculated value: C, 57.65; H, 4.96; N, 10.61

Measured value: C, 57.53; H, 5.03; N, 10.57 fusing points (℃): 188-185 (decomposition) [α] _D+ 138.73 ° of (c=0.395,0.1N-NaOH) inventive embodiments 5:7-(1-amino-3-azabicyclo [3.1.0] hexane-3-yl)-6-fluoro-1-[(2S)-fluoro-(1R)-cyclopropyl]-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid (cut 2)

With cut 2, according to the synthetic described title compound of same procedure described in the inventive embodiments 4.

¹H-NMR(0.1N-NaOD)δ：

0.72-0.74(1H，m)，0.86-0.89(1H，m)，1.44-1.67

(3H，m)，3.39-3.44(2H，m)，3.58(3H，s)，3.72(1H，

d，J＝7.8Hz)，3.83(1H，d，J＝9.8Hz)，4.01-4.06

(1H，m)，5.03-5.06(0.5H，m)，7.66(1H，d，J＝14.16，

Hz)，8.48(1H，s).

Ultimate analysis C ₁₉H ₁₉F ₂N ₃O ₃0.25H ₂O:

Calculated value: C, 57.65; H, 4.96; N, 10.61

Measured value: C, 57.61; H, 4.93; N, 10.72 fusing points (℃): 189-188 (decomposition) [α] _D+ 45.53 ° (c=0.303,0.1N-NaOH) inventive embodiments 6:7-(1-amino-3-azabicyclo [3.2.0] heptane-3-yl)-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid (cut 1)

In methyl-sulphoxide (1.5ml) solution of 1-tertbutyloxycarbonyl-3-azabicyclo [3.2.0] heptane (1.02mm0l), add 1 80mg (0.5mmol) 1-[2-(S)-fluoro-1-(R)-cyclopropyl]-6,7-two fluoro-8-methoxyl groups-1, the boron difluoride acid esters of 4-dihydro-4-Oxoquinoline-3-carboxylic acid and 0.5ml triethylamine stirred 110 hours under room temperature subsequently.Steam except that behind the triethylamine, the gained resistates is mixed with water, and filter and collect the crystallization that is settled out.In collected crystallization, add 15ml 90% methyl alcohol and 3ml triethylamine, refluxed subsequently 4 hours.It is cooled to room temperature, concentrates then.The gained resistates mixed with 10% citric acid and use chloroform extraction.Organic layer water and saturated brine washing are also used anhydrous sodium sulfate drying, steam subsequently to desolventize.The gained resistates is dissolved in methylene dichloride (5ml), and the ice bath cooling was stirred 1 hour under room temperature then down to wherein adding trifluoroacetic acid (5ml).After concentrating, the gained resistates is mixed with concentrated hydrochloric acid and wash with chloroform.Gained solution transfers to pH7.5 with the concentrated sodium hydroxide aqueous solution, uses chloroform extraction then.The extraction liquid anhydrous sodium sulfate drying, steaming subsequently desolventizes.The gained resistates obtains the described title compound of 75.9mg through recrystallization in ethanol. ¹H-NMR(400MHz，0.1N?NaOD)δ：

1.48-1.70(3H，m)，2.03-2.24(3H，m)，2.60(1H，dd，

J＝5.5，13.0Hz)，3.22(1H，d，J＝10.5Hz)，3.53(1H，

dd，J＝5.5，9.5Hz)，3.65-3.71(2H，m)，3.72(3H，

s)，4.07-4.12(1H，m)，4.90-5.10(1H，m)，7.74(1H，

d，J＝13.5Hz)，8.50(1H，s).

Ultimate analysis C ₂₀H ₂₁N ₃O ₄F ₂1/4H ₂O:

Calculated value: C, 58.604; H, 5.286; N, 10.251

Measured value: C, 58.51; H, 5.38; N, 9.94 fusing points (℃): 233-236 inventive embodiments 7:7-(1-amino-3-azabicyclo [3.2.0] heptane-3-yl)-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid (cut 2)

In methyl-sulphoxide (1.5ml) solution of 1-tertbutyloxycarbonyl-3-azabicyclo [3.2.0] heptane (0.778mmol), add 180mg (0.5mmol) 1-[2-(S)-fluoro-1-(R)-cyclopropyl]-6,7-two fluoro-8-methoxyl groups-1, boron difluoride acid esters of 4-dihydro-4-Oxoquinoline-3-carboxylic acid (BF2 inner complex) and 0.5ml triethylamine stirred 115 hours under room temperature subsequently.Steam except that behind the triethylamine, the gained resistates is mixed with water, and filter and collect the crystallization that is settled out.In collected crystallization, add 15ml 90% methyl alcohol and 3ml triethylamine, refluxed subsequently 4 hours.It is cooled to room temperature, concentrates then.The gained resistates mixed with 10% citric acid and use chloroform extraction.Organic layer water and saturated brine washing are also used anhydrous sodium sulfate drying, steam subsequently to desolventize.The gained resistates is dissolved in methylene dichloride (5ml), and the ice bath cooling was stirred 1 hour under room temperature then down to wherein adding trifluoroacetic acid (5ml).After concentrating, the gained resistates is mixed with concentrated hydrochloric acid and wash with chloroform.Gained solution transfers to pH7.5 with the concentrated sodium hydroxide aqueous solution, uses chloroform extraction then.The extraction liquid anhydrous sodium sulfate drying, steaming subsequently desolventizes.The gained resistates obtains the described title compound of 101.6mg through recrystallization in ethanol. ¹H-NMR(400MHz，0.1N?NaOD)δ：

1.34-1.54(3H，m)，1.89-2.02(2H，m)，2.04-2.14

(2H，m)，2.44-2.47(1H，m)，2.92(1H，d，J＝10.5

Hz)，3.35(1H，d，J＝10.5Hz)，3.51-3.56(4H，m)，

3.74(1H，d，J＝10.5Hz)，3.90-3.95(1H，m)，4.70-

4.91(1H，m)，7.57(1H，d，J＝13.5Hz)，8.34(1H，s).

Ultimate analysis C ₂₀H ₂₁N ₃O ₄F ₂:

Calculated value: C, 59.236; H, 5.224; N, 10.369

Measured value: C, 59.28; H, 5.32; N, 10.17 fusing points (℃): 238-240 inventive embodiments 8:5-amino-7-[(3R, 1 ' S)-3-(1-amino-ethyl)-1-pyrrolidyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-Oxoquinoline-3-carboxylic acid

With 626mg (2.92mmol) (3R, 1 ' S)-3-(1-t-butoxycarbonyl amino ethyl) tetramethyleneimine is suspended in the 10ml methyl-sulphoxide, subsequently to wherein adding 437mg (1.46mmol) 5-amino-1-cyclopropyl-6,7-two fluoro-8-methyl isophthalic acids, 4-dihydro-4-Oxoquinoline-3-carboxylic acid and 2.80ml triethylamine heated 21 hours under 150-160 ℃ of nitrogen atmosphere then.After steaming desolventizes, the gained resistates is mixed with chloroform, anhydrous sodium sulfate drying is used in water, 10% aqueous citric acid solution and saturated brine washing then successively.After steaming desolventizes, gained tertiary butyl carbamate compounds is mixed with the 4ml concentrated hydrochloric acid, and mixture was stirred under room temperature 20 minutes,, transfer to pH7.4, use chloroform extraction then with aqueous sodium hydroxide solution with chloroform (50ml * 3) washing.Extraction liquid desolventizes with anhydrous sodium sulfate drying and steaming.The gained resistates obtains the described title compound of 369mg (65%) through recrystallization in alcohol-ether.Fusing point: 106-107 ℃ [α] _D ²⁵=-15.48 (c=0.394,0.1N aqueous sodium hydroxide solutions) ¹H-NMR (400 MHz, 0.1N NaOD) δ:

0.63(1H，brs)，0.75(1H，brs)，1.02-1.18(5H，m)，

1.54-1.58(1H，m)，1.99-2.10(2H，m)，2.29(3H，s)，

2.79(1H，brs)，3.31-3.44(3H，m)，3.58-3.60(1H，

m)，3.91(1H，brs)，8.37(1H，s).

Ultimate analysis C ₂₀H ₂₅N ₄O ₃F1/2H ₂O:

Calculated value: C, 60.44; H, 6.59; N, 14.10

Measured value: C, 60.35; H, 6.55; N, 14.30 inventive embodiments 9:5-amino-7-[(3R, 1 ' S)-3-(1-amino-ethyl)-1-pyrrolidyl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-carboxylic acid

With 394mg (1.84mmol) (3R, 1 ' S)-3-(1-t-butoxycarbonyl amino ethyl) tetramethyleneimine is suspended in the 10ml methyl-sulphoxide, subsequently to wherein adding 317mg (1.00mmol) 5-amino-6,7-two fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-the 8-methyl isophthalic acid, 4-dihydro-4-Oxoquinoline-3-carboxylic acid and 2.00ml triethylamine heated 18 hours under 150-160 ℃ of nitrogen atmosphere then.After steaming desolventizes, the gained resistates is mixed with chloroform, anhydrous sodium sulfate drying is used in water, 10% aqueous citric acid solution and saturated brine washing then successively.After steaming desolventizes, gained tertiary butyl carbamate compounds is mixed with the 3ml concentrated hydrochloric acid, and mixture was stirred under room temperature 10 minutes,, transfer to pH7.4, use chloroform extraction then with aqueous sodium hydroxide solution with chloroform (50ml * 3) washing.Extraction liquid desolventizes with anhydrous sodium sulfate drying and steaming.(chloroform: methyl alcohol: purifying water=7: 3: 1), gained crude product recrystallization in ethanol obtains the described title compound of 118mg (29%) to the gained resistates through preparation TLC.Fusing point: 225-226 ℃ [α] _D ²⁵=-305.07 (c=0.276,0.1 N aqueous sodium hydroxide solutions) ¹H-NMR (400MHz, 0.1N NaOD) δ:

1.11-1.19(4H，m)，1.48-1.59(2H，m)，2.09-2.13

(2H，m)，2.29(3H，s)，2.84(1H，brs)，3.30(1H，br

s)，3.41(1H，brs)，3.52(1H，brs)，3.78(1H，brs)，

3.94(1H，brs)，8.26(1H，2s).

Ultimate analysis C ₂₀H ₂₂N ₄O ₃F ₂9/4H ₂O:

Calculated value: C, 53.74; H, 6.43; N, 12.54

Measured value: C, 53.80; H, 6.02; N, 12.48 reference example C-1:(3R)-ethyl 1-carbobenzoxy-(Cbz) tetramethyleneimine-3-acetic ester

With known 12g (45.9mmol) in the document (3R)-ethyl 1-[(R)-the 1-styroyl] tetramethyleneimine-3-acetic ester is dissolved in the 100ml methylene dichloride, subsequently under room temperature to wherein dripping 7.87ml (55.1mmol) benzyl chloroformate.After dripping, mixture was stirred 16 hours down in uniform temp.After reaction is finished, reaction mixture is concentrated.After this, with gained resistates silica gel column chromatography purifying, through normal hexane: ethyl acetate=5: 1 wash-outs obtains the described title compound of 10.1g (76%) oily. ¹H-NMR(400MHz，CDCl ₃)δ：

1.26(3H，t，J＝7.32Hz)，1.53-1.64(1H，m)，2.07-

2.15(1H，m)，2.36-2.42(2H，m)，2.55-2.67(1H，m)，

3.01-3.07(1H，m)，3.36-3.42(1H，m)，3.49-3.62

(1H，m)，3.67-3.73(1H，m)，4.14(2H，q，J＝7.32

Hz), 5.13 (2H, s), 7.29-7.38 (5H, m). reference example C-2:1-carbobenzoxy-(Cbz)-3-(R)-pyrrolidyl diethyl malonate

With 146mg (0.5mmol) (3R)-ethyl 1-carbobenzoxy-(Cbz) tetramethyleneimine-3-acetic ester is dissolved in the 3ml tetrahydrofuran (THF) (THF), subsequently under-78 ℃ to the 1mol tetrahydrofuran solution that wherein adds 1ml (lmmol) (two trimethyl silyl) ammonification sodium.After uniform temp stirs 30 minutes down, stirred 2 hours down in the 2ml tetrahydrofuran solution that in described reaction soln, drips 0.12ml (1mmol) Vinyl chloroformate under-78 ℃ and in uniform temp.After reaction was finished, Dropwise 5 ml 1N hydrochloric acid was warmed to room temperature subsequently in reaction soln.Reaction soln is mixed with the 40ml ethyl acetate, use the washing of saturated sodium bicarbonate aqueous solution (50ml * 1) and saturated brine (50ml * 1) successively, use dried over mgso then.After steaming desolventized, with gained resistates silica gel column chromatography purifying, through normal hexane: ethyl acetate=4: 1 wash-outs obtained the described title compound of 150mg (83%) oily. ¹H-NMR(400MHz，CDCl ₃)δ：

1.24-1.29(6H，m)，1.60-1.75(1H，m)，2.03-2.19

(1H，m)，2.79-2.91(1H，m)，3.09-3.17(1H，m)，3.28

(1H，d，J＝9.76Hz)，3.32-3.41(1H，m)，3.55-3.65

(1H，m)，3.72-3.77(1H，m)，4.17-4.24(4H，m)，5.13

(2H, s), 7.28-7.59 (5H, m). reference example C-3:1-carbobenzoxy-(Cbz)-3-(R)-pyrrolidyl propanedioic acid hydrogen ethyl ester

177mg (0.49mmol) 1-carbobenzoxy-(Cbz)-3-(R)-pyrrolidyl diethyl malonate is dissolved in 10ml ethanol.Under ice-cooled, in described solution, drip the 10ml ethanolic soln of 32mg (0.49mmol) potassium hydroxide (85%).After dripping, reaction soln was stirred under room temperature 18 hours.After reaction is finished, in reaction soln, add 20ml water, steam then and remove ethanol.Remaining water layer washs with methylene dichloride (50ml * 2), and ether (50ml * 3) extraction is used in the concentrated hydrochloric acid acidifying of gained water layer then.Organic layer is merged and use dried over mgso, steaming desolventizes then, obtains the described title compound of 160mg (97%) oily. ¹H-NMR(400MHz，CDCl ₃)δ：

1.23-1.30(3H，m)，1.63-1.71(1H，m)，2.09-2.20

(1H，m)，2.79-2.90(1H，m)，3.10-3.20(1H，m)，3.28

-3.43(2H，m)，3.51-3.65(1H，m)，3.71-3.84(1H，

m)，4.19-4.25(2H，m)，5.13(2H，s)，7.28-7.55(5H，

M). reference example C-4:2-(1-carbobenzoxy-(Cbz)-3-(R)-pyrrolidyl) ethyl propenoate

1.94g (5.78mmol) 1-carbobenzoxy-(Cbz)-3-(R)-pyrrolidyl propanedioic acid hydrogen ethyl ester and 2.18g (11.56mmol) Eschenmoser salt are dissolved in the 200ml acetonitrile, and solution is mixed with the potassium acetate of catalytically effective amount and reflux 12 hours.After reaction is finished, steam and remove acetonitrile, the gained resistates is mixed with the 200ml ethyl acetate, use 10% citric acid (50ml * 1), 10% sodium sulfite aqueous solution (50ml * 1) and saturated brine (50ml * 1) washing successively.Organic layer with dried over sodium sulfate after, steaming desolventizes.After this, with gained resistates silica gel column chromatography purifying, through normal hexane: ethyl acetate=5: 1 wash-outs obtains the described title compound of 1.12g (64%) oily. ¹H-NMR(400MHz，CDCl ₃)δ：

1.31(3H，t，J＝7.33Hz)，1.53-1.62(1H，m)，1.79-

1.89(1H，m)，2.11-2.21(1H，m)，3.18-3.31(2H，m)，

3.38-3.48(1H，m)，3.51-3.63(1H，m)，4.22(2H，q，

J＝7.33Hz)，5.14(2H，s)，5.58(1H，s)，6.26(1H，d，

J=1.96Hz), and 7.29-7.38 (5H, m). reference example C-5:1-(1-carbobenzoxy-(Cbz)-3-(R)-pyrrolidyl) cyclopropyl-carboxylic acid's ethyl ester

In the mixture of 852mg (2.8mmol) 2-(1-carbobenzoxy-(Cbz)-3-(R)-pyrrolidyl) ethyl propenoate and 5mg (0.02mmol) acid chloride, add the 100ml ether, subsequently at the ice-cooled diethyl ether solution that drips excessive (10 equivalent) diazomethane down.After dripping, reaction mixture was stirred under room temperature 30 minutes.After reaction is finished, steam and to desolventize and with gained resistates silica gel chromatography, through normal hexane: ethyl acetate=3: 1 wash-outs obtains the described title compound of 890mg (quantitatively) oily. ¹H-NMR(400MHz，CDCl ₃)δ：

0.71-0.82(2H，m)，1.19-1.28(5H，m)，1.43-1.59

(1H，m)，1.84-1.95(1H，m)，2.73-2.85(1H，m)，2.93

(1H，dd，J＝10.25Hz，18.55Hz)，3.28-3.39(1H，m)，

3.55-3.75(2H，m)，4.09-4.15(2H，m)，5.13(2H，s)，

7.28-7.36 (5H, m). reference example C-6:1-(1-carbobenzoxy-(Cbz)-3-(R)-pyrrolidyl) cyclopropane-carboxylic acid

5.26g (16.6mm0l) 1-(1-carbobenzoxy-(Cbz)-3-(R)-pyrrolidyl) cyclopropyl-carboxylic acid's ethyl ester is dissolved in 300ml ethanol and solution is cooled off in ice bath, mix, under room temperature, stirred 5 days then with 16.6ml 10N aqueous sodium hydroxide solution.After reaction is finished, steam and remove ethanol, last water layer is with hcl acidifying and use ether (50ml * 4) extraction.Organic layer is merged and use dried over mgso, steaming desolventizes then, obtains the described title compound of 4.95g oily quantitatively. ¹H-NMR(400MHz，CDCl ₃)δ：

0.75-0.85(2H，m)，1.22-1.33(2H，m)，1.45-1.61

(1H，m)，1.82-1.98(1H，m)，2.69-2.78(1H，m)，2.93

-3.01(1H，m)，3.25-3.36(1H，m)，3.55-3.75(2H，

m)，5.12(2H，s)，7.28-7.35(5H，m)，11.09(1H，br

S). reference example C-7:(3R)-1-carbobenzoxy-(Cbz)-3-(1-t-butoxycarbonyl amino cyclopropyl) tetramethyleneimine

289mg (1mmol) 1-(1-carbobenzoxy-(Cbz)-3-(R)-pyrrolidyl) cyclopropane-carboxylic acid is dissolved in the 10ml trimethyl carbinol.Under the room temperature, in this solution, drip 0.28ml (1.3mmol) diphenylphosphoric acid trinitride and 0.24ml (1.6mmol) triethylamine successively, stirred 2 hours down in uniform temp subsequently.After be sure oing to have formed described sour trinitride, temperature of reaction is raise reflux 18 hours.After reaction is finished, steam and to desolventize and, through normal hexane: behind ethyl acetate=4: 1 wash-out, obtain the described title compound of 263mg (73%) oily gained resistates silica gel chromatography. ¹H-NMR(400MHz，CDCl ₃)δ：

0.65-0.85(4H，m)，1.41(9H，s)，1.59-1.75(1H，m)，

1.95-2.00(1H，m)，2.20-2.35(1H，m)，3.07-3.15

(1H，m)，3.27-3.35(1H，m)，3.51-3.65(2H，m)，4.87

(1H，d，J＝10.3Hz)，5.13(2H，s)，7.29-7.37(5H，

m).

[α] _D ²⁵＝6.83，(c＝0.731，CHCl ₃)

When finding after the HPLC assay determination that with chiral column described product is 4: 1 mixture of enantiomers (60%ee).

The condition of this analysis is as described below.

Post: DAICEL CHIRALCEL OD, 25cm * 0.46cm

Mobile phase: normal hexane: Virahol=95: 5

Flow velocity: 1.5ml/min

Temperature: room temperature

Detect: UV (254nm)

The retention time of optical isomer is as described below.

(3R) isomer: 13.06 minutes

(3S) isomer: 15.65 minutes

With described 4: 1 mixtures of 4g recrystallization in acetonitrile, obtain 2.65g described (3R) isomer.[α] _D ²⁵=10.00, (c=0.660, CHCl ₃) reference example D-1:1-ethanoyl cyclopropane carboxylic acid acetoacetic ester

204ml (1.6mol) methyl aceto acetate and 138ml (1.6mol) glycol dibromide are dissolved in 3 liters of N, dinethylformamide, and under room temperature, solution is mixed with 460g (3.3mol) salt of wormwood, stirred 2 days down in uniform temp.After reaction was finished, the filtering insolubles steamed down in the 50mmHg decompression then and removes N, dinethylformamide.The gained resistates is mixed with 1.5 liters of ether, and anhydrous sodium sulfate drying is used in water (500ml * 3) washing then.Steam and remove ether, obtain the described title compound of 113.43g (45%) oily. ¹H-NMR(400?MHz，CDCl ₃)δ：

1.29(3H，t，J＝6.84Hz)，1.47(4H，s)，2.47(3H，s)，

4.21 (2H, q, J=6.84Hz). reference example D-2:1-ethoxycarbonyl-beta-hydroxy-Beta-methyl-cyclopropane ethyl propionate

61.7g (0.39mol) 1-ethanoyl cyclopropane carboxylic acid acetoacetic ester is dissolved in the 500ml benzene, subsequently to the iodine that wherein adds 13g zinc powder and catalytically effective amount.In the time of reflux, the 100ml benzole soln of Dropwise 5 6.2ml (0.51mol) bromoethyl acetate in said mixture when the reaction beginning is violent, suspends dropping, divides aliquot to add the 39g zinc powder, drips remaining bromoethyl acetate benzole soln then.After adding, with reaction soln reflux 2 hours again.Make the reaction soln naturally cooling, with the 500ml1N mixed in hydrochloric acid, then through diatomite filtration.Tell organic layer,, use anhydrous sodium sulfate drying then with saturated brine (500ml * 2) washing.Steaming desolventizes, and obtains the described title compound of 90.31g (95%) oily. ¹H-NMR(400MHz，CDCl ₃)δ：

1.08-1.18(4H，m)，1.23(3H，t，J＝6.84Hz)，1.27

(3H，t，J＝7.33Hz)，1.43(3H，s)，2.91(1H，d，J＝

15.14Hz)，2.98(1H，d，J＝15.14Hz)，4.09(2H，q，J

=6.84Hz), 4.19 (2H, dq, J=1.95Hz, J=6.84Hz). reference example D-3:(E)-ethyl 3-(1-ethoxycarbonyl cyclopropyl)-2-butylene acid esters

90.31g (0.37mol) 1-ethoxycarbonyl-beta-hydroxy-Beta-methyl-cyclopropane ethyl propionate is dissolved in the 182ml pyridine, subsequently in-10 ℃ to-5 ℃ to thionyl chloride wherein.After dripping, it was stirred 3 hours down in uniform temp.After reaction is finished, will extract in 1 liter of frozen water of reaction soln impouring and with methylene dichloride (300ml * 3).Organic layer is merged, use the washing of 1N hydrochloric acid (1 liter * 1) and saturated brine (1 liter * 1) successively, use anhydrous sodium sulfate drying then.Under 0 ℃, Dropwise 5 8ml1 in the gained dichloromethane solution, 8-diazabicyclo [5,4,0]-7-hendecene stirred 18 hours under room temperature subsequently.After reaction was finished, reaction soln was used 1N hydrochloric acid (1 liter * 1) and saturated brine (1 liter * 1) washing successively, uses anhydrous sodium sulfate drying then.After steaming desolventized, with gained resistates silica gel chromatography, through normal hexane: ethyl acetate=9: 1 wash-outs obtained the described title compound of 56.57g (68%) oily. ¹H-NMR(400MHz，CDCl ₃)δ：

1.01(2H，dd，J＝3.91Hz，J＝6.84Hz)，1.24(3H，t，

J＝7.32Hz)，1.28(3H，t，J＝7.32Hz)，1.40(2H，dd，

J＝3.91Hz，J＝6.84Hz)，2.29(3H，d，J＝1.46Hz)，

4.13(2H，q，J＝7.32Hz)，4.16(2H，q，J＝7.32Hz)，

5.78 (1H, d, J=0.98Hz). reference example D-4:4-(1-ethoxycarbonyl cyclopropyl)-1-[(S)-1-styroyl]-the 3-pyrroline-2-one

With 25.37g (0.11mol) (E)-ethyl 3-(1-ethoxycarbonyl cyclopropyl)-2-butylene acid esters is dissolved in the 300ml tetracol phenixin, to the Diisopropyl azodicarboxylate that wherein adds 23.9g (0.13mol) N-bromosuccinimide and catalytically effective amount, refluxed 5 hours down in daylight then subsequently.After reaction is finished, reaction soln is filtered and gained filtrate is concentrated.The resistates that so obtains is dissolved in 250ml ethanol and mixes with 18.83g (0.22mol) sodium bicarbonate.Under the room temperature, to wherein drip 15.84ml (0.12mol) (S)-styroyl amine, after dripping, it was stirred under room temperature 30 minutes, reflux is 4 hours then.After reaction was finished, steaming desolventized and the gained resistates is mixed with the 500ml ethyl acetate, and anhydrous sodium sulfate drying is used in water (500ml * 1), 1N hydrochloric acid (500ml * 2) and saturated brine (500ml * 2) washing then successively.After steaming desolventized, with gained resistates silica gel chromatography, through normal hexane: ethyl acetate=1: 1 wash-out obtained the described title compound of 13.1g (39%) oily. ¹H-NMR(400?MHz，CDCl ₃)δ：

1.13-1.15(2H，m)，1.18(3H，t，J＝6.83Hz)，1.60

(3H，d，J＝7.32Hz)，1.61-1.64(2H，m)，3.80(1H，d，

J＝19.53Hz)，4.09(2H，q，J＝6.83Hz)，4.13(1H，d，

J＝19.53Hz)，5.56(1H，q，J＝7.32Hz)，5.85(1H，t，

J=1.47Hz), 7.25-7.37 (5H, m). reference example D-5:4-(1-ethoxycarbonyl cyclopropyl)-1-[(S)-1-styroyl]-2-Pyrrolidone

With 13.1g (43.8mmol) 4-(1-ethoxycarbonyl cyclopropyl)-1-[(S)-1-styroyl]-the 3-pyrroline-2-one is dissolved in 300ml methyl alcohol, mixes with the 400mg platinum oxide, under nitrogen atmosphere, stirred 18 hours then.After reaction is finished, reaction soln is filtered and concentrates, obtain the described title compound of 13.0g (99%) oily.

Find that through the NMR analyzing and testing this product is (4S): (4R)=3.5: 1 mixture. ¹H-NMR(400MHz，CDCl ₃)δ：

0.63-0.65and0.71-0.73(2H，m)，1.11-1.28(5H，

m)，1.51-1.60(3H，m)，2.14-2.31(1H，m)，2.43-

2.52[(S)-2Hand(R)-1H，m]，2.64-2.76[(S)-2H，m]，

3.14[(R)-2H，d，J＝7.81Hz]，3.48[(S)-1H，t，J＝

8.79Hz]，3.97-4.15(2H，m)，5.49and5.52(1H，each

Q, J=5.86Hz and 6.84Hz), 7.14-7.36 (5H, m). reference example D-6:(4S)-4-(1-ethoxycarbonyl cyclopropyl)-1-[(S)-1-styroyl]-2-tetramethyleneimine thioketones

With 13.04g (43.3mmol) 4-(1-ethoxycarbonyl cyclopropyl)-1-[(S)-1-styroyl]-2-Pyrrolidone is dissolved in 500ml benzene, and with 19.26g (47.6mmol) Lawesson reagent mix, reflux is 1 hour then.After reaction is finished, steam and to desolventize and with gained resistates silica gel chromatography, through normal hexane: ethyl acetate=3: 1 wash-outs obtains a non-enantiomer mixture.Use normal hexane: isopropyl ether=carry out fractional recrystallization at 1: 1 obtains 6.81g (62% (4S) content) the described title compound of needle crystal shape. ¹H-NMR(400MHz，CDCl ₃)δ：

0.63(2H，d，J＝2.44Hz)，1.11-1.23(2H，m)，1.14

(3H，t，J＝7.32Hz)，1.59(3H，d，J＝6.83Hz)，2.68

(1H，dd，J＝8.79Hz，J＝17.48Hz)，2.79(1H，dq，J＝

8.30Hz)，3.02(1H，dd，J＝7.32Hz，J＝11.23Hz)，

3.09(1H，dd，J＝8.79Hz，J＝17.48Hz)，3.76(1H，dd，

J＝8.30Hz，J＝11.23Hz)，4.01(2H，q，J＝7.32Hz)，

6.39 (1H, q, J=6.83Hz), 7.30-7.36 (5H, m). reference example D-7:(3R)-1-carbobenzoxy-(Cbz)-(1-ethoxycarbonyl cyclopropyl) tetramethyleneimine

With 6.81g (21mmol) (4S)-4-(1-ethoxycarbonyl cyclopropyl)-1-[(S)-1-styroyl]-2-tetramethyleneimine thioketones is dissolved in 40ml ethanol, mixes with the 21ml Raney nickel, reflux is 6 hours then.After reaction is finished, reaction soln is filtered, steam then and remove ethanol.The gained resistates is dissolved in the 400ml chloroform, uses 10% ammoniacal liquor (500ml * 2), 0.5N hydrochloric acid (500ml * 2) and saturated brine (500ml * 2) washing successively, use anhydrous sodium sulfate drying then.After steaming desolventizes, the gained resistates is dissolved in the 200ml methylene dichloride, subsequently to wherein dripping 4.57ml (32mmol) benzyl chloroformate.After dripping, with reaction soln reflux 20 hours.After reaction is finished, steam and to desolventize and with gained resistates silica gel chromatography, through normal hexane: ethyl acetate=4: 1 wash-outs obtains the described title compound of 3.62g (54%) oily. ¹H-NMR(400?MHz，CDCl ₃)δ：

0.71-0.82(2H，m)，1.19-1.28(2H，m)，1.43-1.59

(1H，m)，1.84-1.95(1H，m)，2.73-2.85(1H，m)，2.93

(1H，dd，J＝10.25Hz，J＝18.55Hz)，3.28-3.39(1H，

m)，3.55-3.75(2H，m)，4.09-4.15(2H，m)，5.13(2H，

S), 7.28-7.36 (5H, m). reference example E-1:(3R)-the amino cyclopropyl of 1-carbobenzoxy-(Cbz)-3-[1-(N-tertbutyloxycarbonyl-N-methyl)] tetramethyleneimine

With 1.27g (3.52mmol) (3R)-1-carbobenzoxy-(Cbz)-(1-ethoxycarbonyl cyclopropyl) tetramethyleneimine is dissolved in by 22ml methyl iodide and 2ml N, in the mixed solvent that dinethylformamide is formed, mix with 8.2g (35.2mmol) silver suboxide, in airtight test tube, heated 7 hours under 80 ℃ then.After reaction is finished, reaction soln is filtered and gained filtrate is concentrated, with gained resistates silica gel chromatography, through normal hexane: ethyl acetate=3: 1 wash-outs obtains the described title compound of 1.22g (93%) oily. ¹H-NMR(400?MHz，CDCl ₃)δ：

0.55-1.00(4H，m)，1.42，1.44and1.47(9H，eachs)，

1.50-1.69(1H，m)，1.80-1.95(1H，m)，2.25-2.55

(1H，m)，2.81?and?2.84(3H，eachs)，2.98-3.12(1H，

m)，3.24-3.34(1H，m)，3.51-3.65(2H，m)，5.12(2H，

S), 7.30-7.36 (5H, m). reference example E-2:(3R)-the amino cyclopropyl of 1-carbobenzoxy-(Cbz)-3-[1-(N-tertbutyloxycarbonyl-N-ethyl)] tetramethyleneimine

With 1.04g (2.89mmol) (3R)-1-carbobenzoxy-(Cbz)-3-(1-ethoxycarbonyl cyclopropyl) tetramethyleneimine is dissolved in by 11.6ml iodoethane and 1ml N, in the mixed solvent that dinethylformamide is formed, mix with 6.7g (28.9mmol) silver suboxide, in airtight test tube, heated 4 hours under 80 ℃ then.After reaction is finished, reaction soln mixed with ether and through diatomite filtration, gained filtrate is concentrated, and with gained resistates silica gel chromatography, through normal hexane: ethyl acetate=4: 1 wash-outs obtains the described title compound of 831mg (74%) oily. ¹H-NMR(400MHz，CDCl ₃)δ：

0.5-0.98(4H，m)，1.05-1.18(3H，brs)，1.43and

1.46(9H，eachs)，1.47-1.61(1H，m)，1.78-1.93

(1H，m)，2.34-2.53(1H，m)，2.83-3.43(4H，m)，3.48

-3.62 (2H, m), 5.12 (2H, s), 7.32-7.36 (5H, m). reference example E-3:(3R)-the amino cyclopropyl of 3-[1-(benzyloxy ethanoyl)]-1-carbobenzoxy-(Cbz) tetramethyleneimine

Ice bath cooling down, to 1.8g (5.0mmol) (3R)-drip the 10ml trifluoroacetic acid in 1-carbobenzoxy-(Cbz)-3-(1-t-butoxycarbonyl amino cyclopropyl) tetramethyleneimine, subsequently mixture was stirred under room temperature 1 hour.Steam except that behind the trifluoroacetic acid, the gained resistates is mixed with 80ml tetrahydrofuran (THF) and 3.48ml (25mmol) triethylamine, ice-cooled following, to wherein dripping 0.86ml (5.5mmol) the benzyloxy Acetyl Chloride 98Min. that is dissolved in the 20ml tetrahydrofuran (THF).After uniform temp stirs 1 hour down, reaction soln is water (100ml * 1), 10% citric acid (100ml * 1), saturated sodium bicarbonate aqueous solution (100ml * 1) and saturated brine (100ml * 1) washing successively, the organic layer dried over mgso, steaming desolventizes then.The product that is obtained is used for the next step immediately.Reference example E-4:(3R)-and the amino cyclopropyl of 1-carbobenzoxy-(Cbz)-3-[1-(N-2-benzyloxy ethyl-N-tertbutyloxycarbonyl)] tetramethyleneimine

With the amino cyclopropyl of 5mmol (3R)-3-[1-(benzyloxy ethanoyl)]-1-carbobenzoxy-(Cbz) tetramethyleneimine is dissolved in the 10ml tetrahydrofuran (THF), ice-cooled down, to the 1mol tetrahydrofuran solution that wherein drips 30ml (30mmol) borine-tetrahydrofuran (THF) mixture.After dripping, in reaction soln, drip saturated sodium bicarbonate aqueous solution, with the excessive borine of hydrolysis-tetrahydrofuran (THF) mixture.When foam stops to generate, to wherein adding 100ml saturated sodium bicarbonate aqueous solution and 50ml water, and mixture stirred 4 days.Tell the tetrahydrofuran (THF) layer of reaction soln, water layer extracts with ether (100ml * 3).Organic layer is merged, desolventize with dried over mgso and steaming.The gained resistates is dissolved in the 50ml acetonitrile, mixes, under room temperature, stirred 18 hours then with 1.6g (7.5mmol) di-t-butyl carbonic ether.After reaction was finished, steaming desolventized.With gained resistates silica gel chromatography, through normal hexane: ethyl acetate=5: 1 wash-outs obtains the described title compound of 1.31g (53%) oily. ¹H-NMR(400MHz，CDCl ₃)δ：

1.48-1.11(4H，m)，1.21-1.35(1H，m)，1.39?and?1.47

(9H，each?s)，1.79-1.89(1H，m)，2.24-2.69(1H，m)，

2.83-3.69(8H，m)，4.47(2H，s)，5.12(2H，s)，7.29-

7.36 (5H, m). reference example E-5:(3R)-1-[1-(N-tertbutyloxycarbonyl-N-(2-hydroxyethyl) amino) cyclopropyl] tetramethyleneimine

With 772mg (1.56mmol) (3R)-the amino cyclopropyl of 1-carbobenzoxy-(Cbz)-3-[1-(N-2-benzyloxy ethyl-N-tertbutyloxycarbonyl)] tetramethyleneimine is dissolved in 20ml methyl alcohol, mixes with 200mg 5% palladium/carbon, and is warm down at infrared lamp then, 10kg/cm ²Under carried out hydrogenation 36 hours.After reaction was finished, filtering 5% palladium/carbon steamed then and removes methyl alcohol, obtains the described title compound of 413mg (98%).This product is used for described substitution reaction immediately.Reference example F-1:1-t-butoxycarbonyl amino cyclobutane carboxylate

With 1.72g (10.0mmol) 1,1-cyclobutane dicarboxylic acid hydrogen ethyl ester is dissolved in the 20ml trimethyl carbinol, mixes with 3.30g (1.2mmol) diphenylphosphoric acid trinitride and 1.67ml (1.2mmol) triethylamine, and reflux spends the night then.After steaming desolventizes, with the gained resistates through silica gel column chromatography (SiO ₂120ml, hexane: ethyl acetate=20: 1 → 4: 1) purifying obtains the described title compound of 2.11g (87%). ¹H-NMR(CDCl ₃)δ：

1.28(3H，t)，1.43(9H，s)，2.00-2.04(2H，m)，2.31

(2H, brs), 4.22 (2H, dd). reference example F-2:1-t-butoxycarbonyl amino cyclobutane-carboxylic acid

The cyclobutane carboxylate is dissolved in 400ml methyl alcohol with 64.28g (264mmol) 1-t-butoxycarbonyl amino, mixes with 400ml 1N aqueous sodium hydroxide solution, stirs under room temperature then and spends the night.After steaming desolventizes, the gained resistates is mixed with 20% aqueous citric acid solution-chloroform, the gained organic layer desolventizes with anhydrous sodium sulfate drying and steaming, obtains 55.29 (97%) described title compounds. ¹H-NMR(CDCl ₃)δ：

1.45(9H，s)，2.02-2.08(2H，m)，2.26(2H，brs)，2.67

(2H, brs), 5.20 (1H, brs). reference example F-3:1-t-butoxycarbonyl amino-β-oxo tetramethylene ethyl propionate

In 100.0ml ethanol, add 5.0g (0.21mmol) magnesium and 15.0ml tetracol phenixin successively, under room temperature, stirred 1 hour subsequently.To wherein dripping propanedioic acid hydrogen ethyl ester, after stirring 1 hour under the room temperature, steaming desolventizes, and obtains colourless foam shape propanedioic acid magnesium salts.In addition, 55.29g (0.26mmol) 1-t-butoxycarbonyl amino cyclobutane-carboxylic acid is dissolved in 450.0ml THF,, under room temperature, stirred 1.5 hours then with 45.81g (0.28mmol) 1,1 '-carbonyl dimidazoles.In 30 minutes,, under room temperature, stirred 2 days subsequently to the THF solution that wherein drips the above-mentioned magnesium salts of 450.0ml.Steaming desolventizes, and the gained resistates is distributed between 10% aqueous citric acid solution and ethyl acetate, and the gained organic layer with saturated sodium bicarbonate aqueous solution and saturated brine washing, is used anhydrous sodium sulfate drying then.Steaming desolventizes, and obtains described title compound quantitatively. ¹H-NMR(CDCl ₃)δ：

1.26-1.30(2H，m)，1.43(9H，s)，1.87-2.08(4H，m)，

2.66-2.70(2H，m)，3.54(2H，s)，4.20(2H，q)，5.22

(1H, brs). reference example F-4:1-t-butoxycarbonyl amino-beta-hydroxy tetramethylene ethyl propionate

70.21g (257mmol) 1-t-butoxycarbonyl amino-β-oxo tetramethylene ethyl propionate is dissolved in 500.0ml ethanol, under ice-cooled, in batches to wherein adding 4.86g (514mmol) sodium borohydride.Under uniform temp, stir after 2 hours, add entry and steam and desolventize.Gained resistates chloroform extraction with the saturated brine washing, is used anhydrous sodium sulfate drying then.Steaming desolventizes, and obtains the described title compound of 65.25g (93%). ¹H-NMR(CDCl ₃)δ：

1.28(3H，t)，1.44(9H，s)，1.84-2.57(8H，m)，4.17

(2H, q). reference example F-5:1-t-butoxycarbonyl amino tetramethylene ethyl propenoate

65.25g (238mmol) 1-t-butoxycarbonyl amino-beta-hydroxy tetramethylene ethyl propionate is dissolved in 1, and the 000ml methylene dichloride also mixes with 66.30g (476mmol) triethylamine.Under frozen water-brine refrigeration,, stirred 1 hour down in uniform temp subsequently to wherein dripping 23.93ml (7.04mmol) methylsulfonyl chloride.Drip 78.25ml (523.6mmol) 1 in this solution, 8-diazabicyclo [5,4,0] 11-7-alkene raises temperature then gradually, and stirs 5 hours under room temperature subsequently.It is washed anhydrous sodium sulfate drying with 10% aqueous citric acid solution and saturated brine.Steaming desolventizes, and obtains the described title compound of the faint yellow oily of 40.95g (64%). ¹H-NMR(CDCl ₃)δ：

1.28(3H，t)，1.43(9H，s)，1.91-2.05(2H，m)，2.27

(4H，brs)，4.20(2H，q)，5.88(1H，d，J＝15.6Hz)，

7.16 (1H, d, J=15.6Hz). reference example F-6:3-(1-t-butoxycarbonyl amino cyclobutyl) 4-nitro ethyl butyrate

40.95g (152mmol) 1-t-butoxycarbonyl amino tetramethylene ethyl propenoate is dissolved in the 210.0ml Nitromethane 99Min., mixes, under room temperature, stirred 2 days then with 57.2ml (456mol) diphenylphosphoric acid trinitride and 1.67ml (1.2mmol) tetramethyl--guanidine.Steaming desolventizes, and (hexane: ethyl acetate=20: 1 → 3: 1) purifying obtains the described title compound of 26.60g (41%) for silica gel 1,500ml through silica gel column chromatography with the gained resistates. ¹H-NMR(CDCl ₃)δ：

1.26(3H，t)，1.43(9H，s)，1.75-2.22(6H，m)，2.42

(1H，dd，J＝15.6，7.8Hz)，2.56(1H，dd，J＝15.6，4.8

Hz)，4.12(2H，q)，4.21(1H，dd，J＝14.1，7.3Hz)，

4.45 (1H, dd, J=13.1,8.3Hz), 4.70 (1H, brs). reference example F-7:4-(1-t-butoxycarbonyl amino cyclobutyl)-2-Pyrrolidone

20.6g (62.5mmol) 3-(1-t-butoxycarbonyl amino cyclobutyl)-4-nitro ethyl butyrate is dissolved in 500.0ml ethanol, mixes, at room temperature feed then to stir under the hydrogen and spend the night with 40.0ml Raney nickel (R-100 is after water and the washing with alcohol).Behind the filtration catalizer, steaming desolventizes.The gained resistates is dissolved in 200.0ml toluene and reflux spends the night.Behind the naturally cooling, steaming desolventizes, and obtains the described title compound of 15.13g (95%). ¹H-NMR(CDCl ₃)δ：

1.43(9H，s)，1.7-2.6(8H，m)，3.1-3.5(3H，m)，

4.84 (1H, brs), 6.20 (1H, brs). reference example F-8:1-benzyl-4-(1-t-butoxycarbonyl amino cyclobutyl)-2-Pyrrolidone

Under the ice bath cooling, 15.13g (59.5mmol) 4-(1-t-butoxycarbonyl amino cyclobutyl)-2-Pyrrolidone is dissolved in 30.0mlN, dinethylformamide mixes with 2.62g (65.44mmol) sodium hydride (60% oil suspension), stirs 30 minutes under room temperature then.Itself and 7.78ml (65.44mmol) bromotoluene mixed to be incorporated in to stir under the room temperature spend the night.Because also remaining have a part material, further add 1.19g (29.74mmol) sodium hydride and 3.54ml (29.74mmol) bromotoluene and restir 5 hours under room temperature.After steaming desolventizes, the gained resistates is mixed with water, wash with ethyl acetate extraction and with saturated brine.Behind anhydrous sodium sulfate drying, steaming desolventizes.After this, (silica gel 800ml, ethyl acetate: purifying hexane=10: 1 → 1: 1 → 2: 1) obtains the described title compound of 5.65g (28%) through silica gel column chromatography with the gained resistates. ¹H-NMR(CDCl ₃)δ：

1.41(9H，s)，1.69-1.71(1H，m)，1.95-2.19(5H，m)，

2.36(1H，dd，J＝17.0，7.8Hz)，2.52(1H，dd，J＝

17.0，9.2Hz)，2.95-3.29(3H，m)，4.43(2H，AB-q，J

=14.6Hz), 4.77 (1H, brs), 7.22-7.34 (5H, m). reference example F-9:4-(the amino cyclobutyl of 1-)-1-benzyl-2-Pyrrolidone trifluoroacetate

Under the ice bath cooling, Dropwise 5 0.0ml trifluoroacetic acid in 5.65g (16.40mmol) 1-benzyl-4-(1-t-butoxycarbonyl amino cyclobutyl)-2-Pyrrolidone stirred 1 hour under room temperature subsequently.Steam to remove excess reagent, the gained resistates is mixed with toluene and carry out azeotropic and heat, obtain the described title compound of faint yellow oily quantitatively. ¹H-NMR(CDCl ₃)δ：

1.73-2.35(6H，m)，2.55(1H，dd，J＝17.5，7.3Hz)，

2.72(1H，dd，J＝17.5，9.7Hz)，2.83-2.92(1H，m)，

3.33(1H，dd，J＝10.7，6.3Hz)，3.44-3.49(1H，m)，

4.43 (2H, AB-q, J=14.6Hz), 7.14-7.35 (5H, m). reference example F-10:1-benzyl-4-[1-[N '-p-toluenesulfonyl-2-(R)-tetramethyleneimine carbonyl] amino cyclobutyl]-2-Pyrrolidone (cut 1) (cut 2)

5.87g (16.40mmol) 4-(1-amino cyclobutyl)-1-benzyl-2-Pyrrolidone trifluoroacetate is dissolved in 30.0ml methylene dichloride (no stablizer) and mixes with the 13.26ml pyridine.Under ice-cooled, to the 30.0ml dichloromethane solution that wherein drips 7.07g (24.6mol) D-(R)-N-p-toluenesulfonyl pyrophosphoryl chloride.In stir under the room temperature spend the night after, steam and desolventize and excessive pyridine, with gained resistates and 1N mixed in hydrochloric acid and use chloroform extraction.Extraction liquid is used anhydrous sodium sulfate drying then with saturated sodium bicarbonate aqueous solution and saturated brine washing.After steaming desolventized, (silica gel 1kg, ethyl acetate → ethyl acetate: purifying isopropyl ether=50: 1) obtained 3.16g (39%) (cut 1) and 3.33g (41%) (cut 2) to the gained resistates through silica gel column chromatography.Low polarity product (cut 1) ¹H-NMR (CDCl ₃) δ:

1.55-2.37(12H，m)，2.45(3H，s)，2.57(1H，dd，J＝

17.0，9.2Hz)，2.90-2.98(1H，m)，3.10-3.17(1H，

m)，3.25(1H，t，J＝9.7Hz)，3.36(1H，dd，J＝9.7，

5.8Hz)，3.51-3.56(1H，m)，3.85(1H，dd，J＝8.3，

2.9Hz)，4.41(2H，AB-q，J＝14.6Hz)，7.22-7.36(7H，

M), 7.72 (2H, d, J=8.3Hz). high polarity product (cut 2) ¹H-NMR (CDCl ₃) δ:

1.50-2.44(12H，m)，2.45(3H，s)，2.52(1H，dd，J＝

17.0，9.2Hz)，3.03-3.18(3H，m)，3.36(1H，dd，J＝

9.7，8.3Hz)，3.51-3.56(1H，m)，3.88(1H，dd，J＝

8.7，2.9Hz)，4.48(2H，AB-q，J＝14.6Hz)，7.22-7.36

(7H, m), 7.71 (2H, d, J=8.3Hz). reference example F-11:1-benzyl-4-(1-hydrogen basic ring butyl)-2-Pyrrolidone (cut 1)

With 2.40g (4.84mmol) 1-benzyl-4-[1-[N '-p-toluenesulfonyl-2-(R)-tetramethyleneimine carbonyl] amino cyclobutyl]-2-Pyrrolidone (cut 1) mixes with 15ml water and 15ml concentrated hydrochloric acid, and reflux is 2 days then.After the cooling, reaction soln is mixed with 100ml water,, alkalize with aqueous sodium hydroxide solution then with the chloroform washing.It with chloroform (150ml * 4) extraction, is washed and uses anhydrous sodium sulfate drying with saturated brine.Steaming desolventizes, and obtains the described title compound of 1.01g (85%). ¹H-NMR(CDCl ₃)δ：

1.44(2H，brs)，1.58-1.99(6H，m)，2.30-2.38(1H，

m)，2.49-2.56(2H，m)，3.03-3.07(1H，m)，3.28-

3.32(1H，m)，4.45(2H，AB-q，J＝14.6Hz)，7.22-7.35

(5H, m). reference example F-12:1-benzyl-4-(the amino cyclobutyl of 1-)-2-Pyrrolidone (cut 2)

With 2.84g (5.73mmol) 1-benzyl-4-[1-[N '-p-toluenesulfonyl-2-(R)-tetramethyleneimine carbonyl] amino cyclobutyl]-2-Pyrrolidone (cut 2) mixes with 20ml water and 20ml concentrated hydrochloric acid, and reflux is 2 days then.After the cooling, reaction soln is mixed with 100ml water,, alkalize with aqueous sodium hydroxide solution then with the chloroform washing.It with chloroform (150ml * 4) extraction, is washed and uses anhydrous sodium sulfate drying with saturated brine.Steaming desolventizes, and obtains described title compound quantitatively. ¹H-NMR(CDCl ₃)δ：

1.25(2H，brs)，1.59-1.99(6H，m)，2.30-2.37(1H，

m)，2.48-2.58(2H，m)，3.03-3.07(1H，m)，3.26-

3.32(1H，m)，4.45(2H，AB-q，J＝14.6Hz)，7.22-7.35

(5H, m, Ar-H). reference example F-13:1-benzyl-3-(1-t-butoxycarbonyl amino cyclobutyl) tetramethyleneimine (cut 1)

1.01g (4.13mmol) 1-benzyl-4-(the amino cyclobutyl of 1-)-2-Pyrrolidone (cut 1) is dissolved in the 150.0ml tetrahydrofuran (THF), subsequently, under ice-cooled, to wherein add 627mg (16.52mmol) lithium aluminium hydride in batches.Stirring down reflux after 12 hours, reaction soln cool off in ice bath also successively and 627 μ l water) 627 μ l15% aqueous sodium hydroxide solutions and 627 μ l water mix.After stirring 30 minutes under the room temperature, filtering insolubles and steaming desolventize.Under the room temperature, in the gained soup compound, add the 50.0ml acetonitrile, add 1.14ml (4.96mmol) di-t-butyl carbonic ether then, stir subsequently and spend the night.After steaming desolventized, the gained resistates obtained the described title compound of 212mg (16%) through silica gel column chromatography (230-400 order silica gel 100ml, 5% methyl alcohol-chloroform) purifying. ¹H-NMR(CDCl ₃)δ：

1.45-1.98(15H，m)，2.06-2.20(2H，m)，2.47-2.52

(1H，m)，2.75-3.01(4H，m)，3.57(2H，s)，5.15(1H，

Brs), and 7.22-7.37 (5H, m). reference example F-14:1-benzyl-3-(1-t-butoxycarbonyl amino cyclobutyl) tetramethyleneimine (cut 2)

1.50g (6.14mmol) 1-benzyl-4-(the amino cyclobutyl of 1-)-2-Pyrrolidone (cut 2) is dissolved in the 200.0ml tetrahydrofuran (THF), subsequently, in the ice bath cooling down, to wherein add 932mg (24.56mmol) lithium aluminium hydride in batches.Stir following reflux after 12 hours, reaction soln is cooled off in ice bath also mix with 932 μ l water, 932 μ l15% aqueous sodium hydroxide solutions and 932 μ l water successively.After stirring 30 minutes under the room temperature, filtering insolubles and steaming desolventize.Under the room temperature, in the gained soup compound, add the 70.0ml acetonitrile, add 1.69ml (7.37mmol) di-t-butyl carbonic ether then, stir subsequently and spend the night.After steaming desolventized, the gained resistates obtained the described title compound of 525mg (26%) through silica gel column chromatography (230-400 order silica gel 150ml, 5% methyl alcohol-chloroform) purifying. ¹H-NMR(CDCl ₃)δ：

1.45-1.96(15H，m)，2.06-2.20(2H，m)，2.47-2.52

(1H，m)，2.75-3.01(4H，m)，3.57(2H，s)，4.21(1H，

Brs), and 7.25-7.37 (5H, m). reference example F-15:3-(1-t-butoxycarbonyl amino cyclobutyl) tetramethyleneimine (cut 1)

212mg (0.65mmol) 1-benzyl-3-(1-t-butoxycarbonyl amino cyclobutyl) tetramethyleneimine (cut 1) is dissolved in 20.0ml ethanol, mixes being incorporated in infrared lamp warm time with 200mg 10% palladium/carbon, stirred 3 hours under 4 hydrogen-pressure.Behind the filtration catalizer, steaming desolventizes, and obtains the described title compound of 136mg (88%).Reference example F-16:3-(uncle's 1-fourth oxygen carboxyamino cyclobutyl) tetramethyleneimine (cut 2)

525mg (1.59mmol) 1-benzyl-3-(1-t-butoxycarbonyl amino cyclobutyl) tetramethyleneimine (cut 2) is dissolved in 50.0ml ethanol, mixes being incorporated in infrared lamp warm time with 500mg 10% palladium/carbon, stirred 3 hours under 4 hydrogen-pressure.Behind the filtration catalizer, steaming desolventizes, and obtains described title compound quantitatively.Reference example G-1:1-diphenyl-methyl-3-(tolysulfonyl oxygen base) azetidine

In being dissolved in 1-diphenyl-methyl-3-hydroxy azetidine in the 20ml pyridine, 2.39g (10mmol) adds 1.46g (12mmol) Dimethylamino pyridine.Under-40 ℃, to wherein adding 12.10g (11mmol) Tosyl chloride, elevated temperature and under room temperature, stirring 1 day gradually subsequently.It is mixed with 150ml water,, use anhydrous sodium sulfate drying then with chloroform (100ml * 3) extraction.After steaming desolventized, (the 250ml ethyl acetate: purifying hexane=1: 2) obtained the described title compound of 2.88g (73%) to the gained resistates through silica gel column chromatography. ¹H-NMR(CDCl ₃)δ：

2.42(3H，s)，3.02-3.06(2H，m)，3.43-3.47(2H，m)，

4.32(1H，s)，4.86-4.89(1H，m)，7.15-7.76(14H，

M). reference example G-2:(1-benzhydryl-3-aza ring butane group) diethyl malonate

Under the room temperature, in 17.90g (111.80mmol) is dissolved in diethyl malonate in the 250ml tetrahydrofuran (THF), add 4.07g (101.75mmol) 60% sodium hydride, stirred subsequently 2 hours.After this, be dissolved in 1-diphenyl-methyl-3-(tolysulfonyl oxygen base) azetidine in the 90ml tetrahydrofuran (THF), 1 week of reflux subsequently to wherein adding 20g (50.82mmol).Reaction soln is mixed with 10% aqueous citric acid solution, steam then and remove tetrahydrofuran (THF).The gained resistates is mixed with saturated sodium bicarbonate aqueous solution, extract and use anhydrous sodium sulfate drying with chloroform (200ml * 3).After steaming desolventized, (230-400 order silica gel 450ml, ethyl acetate: purifying hexane=1: 3) obtained described title compound to the gained resistates quantitatively through silica gel column chromatography. ¹H-NMR(CDCl ₃)δ：

1.21(6H，t，J＝7.3Hz)，2.89-2.92(2H，m)，2.97-

3.05(1H，m)，3.35-3.39(2H，m)，3.64(1H，d，J＝

10.2Hz)，4.14(4H，dd)，4.32(1H，s)，7.14-7.38

(10H, m). reference example G-3:(1-carbobenzoxy-(Cbz)-3-azetidinyl) diethyl malonate

In 3.40g (8.91mmol) is dissolved in (1-benzhydryl-3-aza ring butane group) diethyl malonate in the 30ml methylene dichloride, add 1.91ml (13.36mmol) benzyl chloroformate, under room temperature, stir subsequently and spend the night.After steaming desolventized, resistates obtained the described title compound of 2.64g (84%) through silica gel column chromatography (250ml, 3-5% methyl alcohol-methylene dichloride) purifying. ¹H-NMR(CDCl ₃)δ：

1.25(6H，t)，3.16-3.19(1H，m)，3.62(1H，d，J＝

11.7Hz)，3.79-3.83(2H，m)，4.16-4.22(4H，m)，

5.08 (2H, s), 7.31-7.35 (5H, m). reference example G-4:(1-carbobenzoxy-(Cbz)-3-azetidinyl) propanedioic acid hydrogen ethyl ester

Be dissolved in to 13.43g (38.33mmol) and add the 38.44ml1N potassium hydroxide-ethanol solution in (1-carbobenzoxy-(Cbz)-3-azetidinyl) diethyl malonate in the 130ml ethanol, under room temperature, stir subsequently and spend the night.After steaming desolventizes, the gained resistates is mixed with 10% aqueous citric acid solution,, use anhydrous sodium sulfate drying then with chloroform (200ml * 3) extraction.Steaming desolventizes, and obtains described title compound quantitatively. ¹H-NMR(CDCl ₃)δ：

1.27(3H，t)，3.17-3.22(1H，m)，3.66(1H，d，J＝

10.7Hz)，3.83(2H，dd，J＝5.8，8.7Hz)，4.17-4.24

(4H, m), 5.09 (2H, s), 7.33-7.34 (5H, m). reference example G-5:2-(1-carbobenzoxy-(Cbz)-3-azetidinyl) ethyl propenoate

Add the potassium acetate of 1.05g (5.67mmol) Eshenmoser salt and catalytically effective amount in 732mg (2.28mmol) is dissolved in (1-carbobenzoxy-(Cbz)-3-azetidinyl) propanedioic acid hydrogen ethyl ester in the 70ml acetonitrile, reflux is 4.5 hours subsequently.After steaming desolventizes, the gained resistates is mixed with the 100ml ethyl acetate, with 10% aqueous citric acid solution, 10% sodium sulfite aqueous solution and saturated brine washing, use anhydrous sodium sulfate drying then successively.Steaming desolventizes, and obtains the described title compound of 569mg (86%). ¹H-NMR(CDCl ₃)δ：

1.29(3H，t)，3.60-3.64(1H，m)，3.91-3.95(2H，m)，

4.18-4.25(4H，m)，5.09(2H，s)，5.66(1H，d，J＝1.9

Hz), 6.36 (1H, d, J=1.4Hz), 7.29-7.36 (5H, m). reference example G-6:1-(1-carbobenzoxy-(Cbz)-3-azetidinyl) cyclopropane carboxylic acid acetoacetic ester

In being dissolved in trimethylammonium sulfoxonium iodide in the 10ml methyl-sulphoxide, 1.27g (5.76mmol) adds 192mg (4.80mmol) 60% sodium hydride, under room temperature, stirred 15 minutes subsequently, be dissolved in 2-(1-carbobenzoxy-(Cbz)-3-azetidinyl) ethyl propenoate in the 10ml methyl-sulphoxide to wherein adding 1.39g (4.80mmol) then.The gained mixture was stirred under room temperature 4 hours, stirred 1 hour down in 100 ℃ then.Reaction soln mixed with the 200ml saturated brine and with ethyl acetate (100ml * 3) extraction, organic layer washs and use anhydrous sodium sulfate drying with saturated brine (100ml * 2).After steaming desolventized, (100ml, ethyl acetate: purifying hexane=1: 2) obtained the described title compound of 536mg (37%) to the gained resistates through silica gel column chromatography. ¹H-NMR(CDCl ₃)δ：

0.84(2H，s)，1.20-1.25(5H，m)，3.26-3.28(1H，m)，

3.54(2H，brs)，4.0?5-4.13(4H，m)，5.08(2H，s)，7.32

-7.35 (5H, m). reference example G-7:1-(1-carbobenzoxy-(Cbz)-3-azetidinyl) cyclopropane-carboxylic acid

Be dissolved in to 2.68g (8.83mmol) and add 27ml 1N aqueous sodium hydroxide solution in 1-(1-carbobenzoxy-(Cbz)-3-azetidinyl) the cyclopropane carboxylic acid acetoacetic ester in the 27ml ethanol, under room temperature, stir subsequently and spend the night.After steaming desolventizes, the gained resistates is mixed with 10% citric acid,, use anhydrous sodium sulfate drying then with chloroform (50ml * 3) extraction.Steaming desolventizes, and obtains the described title compound of 2.35g (97%). ¹H-NMR(CDCl ₃)δ：

0.93(2H，s)，1.31(2H，d，J＝2.4Hz)，3.24-3.28

(1H，m)，3.54(2H，brs)，4.06(2H，brs)，5.08(2H，s)，

7.30-7.37 (5H, m). reference example G-8:1-carbobenzoxy-(Cbz)-3-(1-t-butoxycarbonyl amino cyclopropyl) azetidine

2.35g (8.54mmol) 1-(1-carbobenzoxy-(Cbz)-3-azetidinyl) cyclopropane-carboxylic acid is dissolved in the 40ml trimethyl carbinol and mixes, then the mixture reflux is spent the night with 3.52g (12.7mmol) diphenylphosphoric acid trinitride and 2.38ml (17.07mmol) triethylamine.After steaming desolventized, (silica gel 600ml, hexane: ethyl acetate=2: 3) purifying obtained the described title compound of 1.84g (62%) to the gained resistates through silica gel column chromatography. ¹H-NMR(CDCl ₃)δ：

0.75(2H，s)，0.83(2H，s)，1.41(9H，s)，2.82-2.89

(1H，m)，3.71(2H，brs)，4.22(2H，t，J＝8.7Hz)，5.06

(1H, brs), 5.08 (2H, s), 7.2 8-7.34 (5H, m). reference example G-9:3-(1-t-butoxycarbonyl amino cyclopropyl) azetidine

Be dissolved in to 1.84g (5.31mmol) and add 1.5g 10% palladium/carbon in 1-carbobenzoxy-(Cbz)-3-(1-t-butoxycarbonyl amino cyclopropyl) azetidine in the 100ml ethanol, catalytic hydrogenation is spent the night under atmospheric pressure at room subsequently.Behind the filtration catalizer, steaming desolventizes, and obtains described title compound quantitatively. ¹H-NMR(CDCl ₃)δ：

0.79(2H，brs)，0.87(2H，s)，1.44(9H，s)，1.78(1H，

brs)，3.00(1H，brs)，4.01(4H，d，J＝7.8Hz)，5.29

(1H, brs). reference example H-1:3,4,5,6-ptfe dimethyl phthalate

In the ice bath cooling down, be dissolved in 3,4,5 in the methyl alcohol, add 300ml sulfuric acid in the 6-ptfe phthalate, refluxed subsequently 3 days to 300g (1.26mol).After being chilled to room temperature, filter the crystallization that collecting precipitation goes out.In filtrate, steam, the gained resistates is mixed the crystallization that collecting precipitation goes out with 2 liters of frozen water except that behind the methyl alcohol.The crystallization that merges is washed with water, dry then, obtain the partially purified product of the described title compound of 294.86g. ¹H-NMR(400MHz，CDCl ₃)δ：

0.95 (6H, s). reference example H-2:4-diethoxy carbonyl methyl-3,5,6-trifluoro-phthalic acid dimethyl ester

Be dissolved in 3,4,5 in the 750ml dimethyl formamide to 286.4g (1.077mol), add 164ml (1.08mol) diethyl malonate and 414.63g (3mol) salt of wormwood in the 6-ptfe dimethyl phthalate, under room temperature, stirred 26 hours subsequently.Reaction mixture is filtered,, extract in the 200ml4N hydrochloric acid and with ether (1 liter * 2) filtrate impouring 1.Anhydrous sodium sulfate drying is used in gained organic layer water (1 liter * 2) and saturated brine (1 liter) washing then.Steaming desolventizes, and obtains the partial purification product of the described title compound of 433.61g (1.068mol, 99.2%). ¹H-NMR(400?MHz，CDCl ₃)δ：

1.29(6H，t，J＝7.5Hz)，3.92(3H，s)，3.96(3H，s)，

4.28 (4H, q, J=7.5Hz), 4.98 (1H, s). reference example H-3:4-carboxymethyl-3,5,6-trifluoro-phthalic acid

2 liter of 60% sulfuric acid is joined 433.6g (1.068mol) 4-diethoxy carbonyl methyl-3,5, in the 6-trifluoro-phthalic acid dimethyl ester, stirred 40 hours down in 110 ℃ subsequently.After being chilled to room temperature, will extract in its impouring 1 premium on currency and with ethyl acetate (1 liter * 3).Organic layer is used dried over sodium sulfate then with 1 premium on currency and 1 liter of saturated brine washing.After steaming desolventizes, obtain the partial purification product of the described title compound of 304.35g. ¹H-NMR(400MHz，D ₂O)δ：

3.77 (2H, s). reference example H-4:2,4,5-three fluoro-3-tolyl acids

Be dissolved in 1.5 liters of 4-carboxymethyls-3,5 in the methyl-sulphoxide to 304.35g, add 0.5 liter of triethylamine in the 6-trifluoro-phthalic acid, stirred 64 hours down in 140 ℃ subsequently.After being chilled to room temperature, steaming and remove methyl-sulphoxide.Gained resistates and 1 liter of 1N mixed in hydrochloric acid are also extracted with ether (1 liter * 3).Organic layer is used dried over sodium sulfate then with 1 premium on currency and 1 liter of saturated brine washing.Steaming desolventizes, and obtains the partial purification product of the described title compound of 177.94g (0.64mol, 60%). ¹H-NMR(4?00?MHz，CDCl ₃)δ：

2.29(3H，t，J＝1.5Hz)，7.70(1H，dt，J＝6.5，9.5

Hz). reference example H-5:2,4,5-three fluoro-3-methyl-6-nitrobenzoic acids

Ice-cooled with 43.4g (0.21mol) 2,4,5-three fluoro-3-tolyl acids join in the 120ml vitriol oil down, and the speed that is no more than 30 ℃ with temperature of reaction is to wherein dripping nitrosonitric acid (d1.52).After dripping, it was stirred under room temperature 1 hour.After reaction is finished, in 1.5 liters of frozen water of reaction soln impouring, filter and collect the crystallization that generates.The crystallization water (100ml * 3) that is obtained washed and be dissolved in 500ml ethyl acetate, solution anhydrous sodium sulfate drying.The above-mentioned filtrate that obtains is extracted and uses anhydrous sodium sulfate drying with chloroform (300ml * 4).After this, with organic layer merging and concentrated, obtain the described title compound of 50.3g (quantitatively). ¹H-NMR(400MHz，CDCl ₃)δ：

2.36 (3H, t, J=2.44Hz). reference example H-6:2,4,5-three fluoro-3-methyl-6-nitro benzoyl ethyl acetate

With 2,4,5-three fluoro-3-methyl-6-nitrobenzoic acids are suspended in the 490ml benzene, subsequently, under room temperature to wherein dripping 30.4ml (0.42mol) thionyl chloride.After dripping, with reaction soln reflux 22 hours.Steam except that behind the benzene, gained resistates and 200ml benzene are carried out twice azeotropic processing, obtain 2,4,5-three fluoro-3-methyl-6-nitrobenzoyl chloride crude product.6.13g (0.25mol) magnesium and 200ml ethanol are mixed, to wherein dripping the 10ml tetracol phenixin, stirred 6 hours down in uniform temp subsequently under the room temperature.After magnesium dissolving, be dissolved in diethyl malonate in the 150ml tetrahydrofuran (THF) to wherein adding 44ml (0.29mol), continue 1 hour.After dripping, mixture was stirred under room temperature 2 hours.After reaction was finished, steaming desolventized and is following to gained resistates drying in decompression.The gained solid is mixed with the 300ml tetrahydrofuran (THF), subsequently the introversive 150ml tetrahydrofuran solution that wherein drips above-mentioned gained acyl chlorides in 1.5 hours.After dripping, reaction soln was stirred under room temperature 2 hours.After reaction is finished, reaction soln mixed with the 400ml ethyl acetate and use 10% citric acid (500ml * 1), water (500ml * 1) and saturated brine (500ml * 1) to wash successively, organic layer with anhydrous sodium sulfate drying also steaming desolventize.The gained resistates is mixed with 1.5 premium on currency and 1.5 liters of tosic acid, and in the heating down 1.5 hours that refluxes.After reaction is finished, make the reaction soln naturally cooling and use benzene (500ml * 5) extraction.Merge organic layer, wash and use anhydrous sodium sulfate drying with the 500ml saturated brine.After steaming desolventizes, the gained resistates is carried out silica gel chromatography, through hexane: ethyl acetate=95: 5 wash-outs obtains the described title compound of 37.65g (44%). ¹H-NMR(400MHz，CDCl ₃)δ：

1.26 and 1.34 (3H, each t, J=7.33Hz), 2.33 and 2.35

(3H, each t, J=2.44Hz), 3.90 (1.35H, s), 4.20 Hes

4.28(2H，each?q，J＝7.33Hz)，5.48(0.325H，s)，12.34

(0.325H, s). reference example H-7:6,7-two fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-5-nitro-4-Oxoquinoline-3-carboxylic acid ethyl ester

To 16.4g (53.8mmol) 2,4, add 17.9ml (107.6mmol) ethyl orthoformate and 29ml diacetyl oxide in 5-three fluoro-3-methyl-6-nitro benzoyl ethyl acetate, stirred 2 hours down in 100 ℃ subsequently.Steaming desolventizes, with the gained resistates be dissolved in 200ml toluene and with 16g (64.7mmol) (1R, 2S)-tosilate of 2-fluorine cyclopropylamine mixes.Ice bath cooling is dissolved in triethylamine in the 30ml toluene to wherein dripping 10.87ml (78mmol) down.After dripping, it was stirred 2 hours down in uniform temp.Reaction soln is mixed with the 200ml ethyl acetate and water (500ml * 1) and saturated brine (500ml * 2) washing successively, and organic layer desolventizes with anhydrous sodium sulfate drying and steaming.The gained resistates is dissolved in 150ml 1, and the 4-diox is subsequently ice-cooled following, to wherein add 3.23g (80.7mmol) sodium hydride in batches.After stirring 1 hour under the room temperature, with the reaction soln impouring in ice bath in the refrigerative 0.5N hydrochloric acid.Filter and collect the crystallization that is generated, water (100ml * 3) washing, recrystallization in chloroform-ethanol obtains the described title compound of 13.9g (70%) then.Fusing point: 230-231 ℃ ¹H-NMR (400MHz, CDCl ₃) δ:

1.38(3H，t，J＝7.33Hz)，1.35-1.45(1H，m)，1.58-

1.70(1H，m)，2.75(3H，d，J＝3.42Hz)，3.85-3.93

(1H，m)，4.37(2H，q，J＝7.33Hz)，4，80-4.83and

4.95-4.99 (1H, m), 8.57 (1H, d, J=2.93Hz). reference example H-8:5-amino-6,7-two fluoro-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-carboxylic acid ethyl ester

With 3.91g (37.6mmol) 6,7-two fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-5-nitro-4-Oxoquinoline-3-carboxylic acid ethyl ester is suspended in 1 liter of methyl alcohol and 1, in 1: 1 mixed solution of 4-diox, itself and mixed being incorporated under the room temperature of 200ml Raney nickel were stirred 10 minutes.After reaction is finished, reaction soln is filtered and gained filtrate is concentrated.The gained resistates is dissolved in the 300ml chloroform and, filtrate concentrated, obtain the described title compound of 12.5g (98%) through diatomite filtration. ¹H-NMR(400?MHz，CDCl ₃)δ：

1.25-1.38(1H，m)，1.39(3H，t，J＝7.33Hz)，1.45-

1.59(1H，m)，2.46(3H，d，J＝2.44Hz)，3.73-3.79

(1H，m)，4.38(2H，q，J＝7.33Hz)，4.73-4.75and

4.88-4.92(1H，m)，6.99(2H，brs)，8.40(1H，d，J＝

3.42Hz).

Ultimate analysis C ₁₆H ₁₃F ₃N ₂O ₅1/4H ₂O:

Calculated value: C51.28 H3.63 N7.47

Measured value: C51.51 H3.58 N7.43 reference example H-9:5-amino-6,7-two fluoro-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-carboxylic acid

With 10.43g (30.6mmol) 5-amino-6,7-two fluoro-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-carboxylic acid ethyl ester mixes with 150ml acetate and 150ml concentrated hydrochloric acid, and reflux is 1 hour then.After reaction is finished, make the reaction soln naturally cooling and mix the crystallization that the filtration collection generates, water (100ml * 2), ethanol (300ml * 1) and ether (300ml * 1) washing successively with 700ml water, dry then, obtain the described title compound of 7.52g (79%).Fusing point: 293-297 ℃ (decomposition) ¹H-NMR (400MHz, 0.1N NaOD) δ:

1.31-1.42(1H，m)，1.53-1.68(1H，m)，2.52(3H，s)，

4.03-4.10(1H，m)，4.85-4.93and5.05-5.10(1H，

M), 8.32 (1H, s). reference example I-1:2,3,4,5,6-penta fluoro benzene formyl radical ethyl acetate

The mixture reflux that 100g (0.47mol) pentafluorobenzoic acid, 900ml benzene and 350ml (4.80mol) thionyl chloride are constituted 40 hours.After reaction is finished, solution decompression is concentrated, after benzene (900ml * 2) repeated evaporation, the gained resistates is dissolved in the 500ml ether.The mixture that 11.5g (0.47mol) magnesium, 450ml ethanol and 20ml tetracol phenixin are constituted stirred under room temperature 1 hour, and was dissolved in diethyl malonate in the 900ml ether to wherein dripping 71.6ml (0.47mol).Stir after 17 hours under uniform temp, with the reaction soln evaporated under reduced pressure, resistates is dissolved in 1, and the 500ml ether to wherein dripping above-mentioned acyl chlorides, stirred 63 hours down in uniform temp under the room temperature subsequently.After reaction was finished, reaction soln was used 10% citric acid and water washing successively, uses anhydrous sodium sulfate drying then, steamed subsequently to desolventize.Resistates is mixed with 300ml water and 1.00g (5.81mol) tosic acid, reflux 6 hours, with 2,500ml benzene mixes, and washes with water then.Organic layer desolventizes with anhydrous sodium sulfate drying and steaming.The gained resistates obtains the described title compound of 89.7g (67%) through underpressure distillation (10mmHg, 118-120 ℃) purifying.Reference example I-2:5,6,7,8-tetrafluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester

With 14.4g (51.0mmol) 2,3,4,5,6-penta fluoro benzene formyl radical ethyl acetate is dissolved in 150ml benzene, and with 28.8ml (204mmol) N, the dinethylformamide dimethyl carbonyl that contracts mixes, and reflux is 3 hours then.After reaction was finished, steaming desolventized.With gained resistates and 120ml toluene and 12.6g (51.0mmol) (1R, 2S)-2-fluoropropyl amine tosilate and mix to be incorporated in the ice bath and cool off, subsequently to toluene (39ml) solution that wherein drips 8.54mll (61.2mmol) triethylamine.After dripping, it was stirred under room temperature 1 hour.After reaction is finished, reaction soln is filtered through suction strainer, filtrate water (50ml * 3) washing, water layer extracts with ethyl acetate (100ml * 3) then.Organic layer is merged, with the saturated brine washing, use anhydrous sodium sulfate drying then, steaming subsequently desolventizes.Under the ice bath cooling, with resistates and 100ml 1, the 4-diox mixes, and mixes with 2.04g (51.0mmol) 60% sodium hydride, stirs 2 hours under room temperature subsequently.After reaction is finished, will extract in reaction soln impouring 10% citric acid and with methylene dichloride (200ml * 2).Organic layer is with the saturated brine washing and use anhydrous sodium sulfate drying, steams subsequently to desolventize.With the crystallization in methylene dichloride-isopropyl ether of gained resistates.Filter and collect the crystallization that generates, use the ether thorough washing, drying under reduced pressure obtains the described title compound of 12.6g (71%) then. ¹H-NMR(400MHz，CDCl ₃)δ：

8.46(1H，s)，5.02-4.80(1H，m)，4.37(2H，q，J＝

7.32Hz)，3.83-3.75(1H，m)，1.75-1.55(2H，m)，

1.40 (3H, t, J=7.32Hz). and reference example I-3:5-benzyloxy-6,7,8-three fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester

With 2.35g (6.77mmol) 5,6,7,8-tetrafluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester is dissolved in 20ml toluene and mixes with 0.70ml (6.77mmol) benzylalcohol.After being chilled to 0 ℃, it is further mixed with 60% sodium hydride that 280mg (6.99mmol) is suspended in the 10ml toluene, mixture was stirred 2 hours down in uniform temp, under room temperature, stirred 2 hours then.After reaction is finished, reaction soln is mixed with 10% citric acid and extract with chloroform (100ml * 2).Organic layer desolventizes with anhydrous sodium sulfate drying and steaming.(hexane: ethyl acetate=1: 1) purifying obtains the described title compound of 1.68g (57%) to the gained resistates through silica gel column chromatography. ¹H-NMR(400?MHz，CDCl ₃)δ：

8.41(1H，s)，7.62-7.28(5H，m)，5.25and5.19(2H，

ABd，J＝10.25Hz)，5.00-4.77(1H，m)，4.39(2H，q，

J＝7.33Hz)，3.82-3.72(1H，m)，1.70-1.53(2H，m)，

1.39 (3H, t, J=7.33Hz). and reference example I-4:6,7,8-three fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-5-hydroxyl-4-Oxoquinoline-3-carboxylic acid ester

With 1.68g (3.86mmol) 5-benzyloxy-6,7,8-three fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1, heating was 1 hour under 4-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester and 15ml acetate-water-sulfuric acid mixture (8: 6: 1) mixed and be incorporated in 100 ℃.Reaction soln is chilled to room temperature and mixes, filter and collect the crystallization that generates with 20ml water, the water thorough washing, drying under reduced pressure obtains the described title compound of 1.04g (85%) then. ¹H-NMR(400?MHz，CDCl ₃)δ：

13.11(1H，s)，13.10-12.75(1H，br)，8.82(1H，s)，

5.09-4.83(1H，m)，3.99-3.88(1H，m)，1.86-1.69

(2H, m). inventive embodiments 10:5-amino-7-[(3R)-3-(the amino cyclopropyl of 1-)-1-pyrrolidyl]-6,8-two fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid hydrochloride

278.8mg (1.25mmol) 1-carbobenzoxy-(Cbz)-3-(1-t-butoxycarbonyl amino cyclopropyl) tetramethyleneimine is suspended in the 10ml acetonitrile, subsequently to wherein adding 194.8mg (0.62mmol) 5-amino-6,7,8-three fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid and 0.60ml (4.30mmol) triethylamine, reflux is 11 hours then.After steaming desolventizes, the gained resistates is mixed with chloroform, anhydrous sodium sulfate drying is used in water, 10% aqueous citric acid solution and saturated brine washing then successively, steams subsequently to desolventize.(low layer chloroform: methyl alcohol: expansion twice water=7: 3: 1) obtains a yellow oil and solid mixture through silica gel thin-layer chromatography with the gained resistates.The tertiary butyl carbamate compounds that so obtains is cooled off in sodium-chlor-ice bath, and to wherein dripping the 8.0ml trifluoroacetic acid.Stirring is after 20 minutes down in uniform temp, and steaming removes trifluoroacetic acid, and the gained resistates is washed three times by decantation after adding ether.The khaki powder that so obtains is dissolved in the 1N aqueous sodium hydroxide solution, with hydrochloric acid solution is transferred to pH7.4, with chloroform-methanol (10: 1) extraction, use anhydrous sodium sulfate drying then, steaming subsequently desolventizes.The gained resistates is mixed with ether, and the powder that is generated is dissolved in ethanol, mix, under room temperature, stir then with hydrochloric acid-ether.After steaming desolventized, the gained resistates washed three times by decantation after adding ether, with gained yellow solid recrystallization in ethanol, obtains the described title compound of 55.7mg (26.2) yellow powder shape.Fusing point: 240.0-260.0 ℃ ¹H-NMR (D ₂O) δ:

0.75-0.95(4H，m)，1.22-1.60(3H，m)，1.86-2.02

(1H，m)，2.40-2.62(1H，m)，3.18-3.40(1H，m)，3.40

-3.82 (4H, m), 4.65-4.98 (1H, m), 8.20 (1H, s). inventive embodiments 11:7-[(3R)-3-(the amino cyclopropyl of 1-)-1-pyrrolidyl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-carboxylic acid

With 433mg (1.2mmol) (3R)-1-carbobenzoxy-(Cbz)-3-(1-t-butoxycarbonyl amino cyclopropyl) tetramethyleneimine is dissolved in 10ml methyl alcohol, subsequently to wherein adding 100mg 5% palladium/carbon, carries out hydrogenation 2 hours at infrared lamp under the warm and normal pressure.After reaction is finished, filtering 5% palladium/carbon also steams and removes methyl alcohol, the gained resistates is dissolved in 10ml methyl-sulphoxide (DMSO), subsequently to wherein adding 0.174ml (1.25mmol) triethylamine and 217mg (0.6mmol) 6,7-two fluoro-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-carboxylic acid BF2 inner complex stirred 25 hours under room temperature then.After reaction is finished, steam and remove DMSO, the gained resistates is mixed with water, filter and collect crystallization and water (10ml * 4) washing that is generated.The gained crystallization is dissolved in 20ml methyl alcohol and the 5ml water, and solution is mixed with the 0.3ml triethylamine, reflux 4.5 hours.After reaction is finished, reaction soln is mixed with 50ml water, steam and remove methyl alcohol, then the gained resistates is extracted with chloroform (50ml * 2).Organic layer is merged and use dried over sodium sulfate, steaming desolventizes.The ice bath cooling drips the 10ml concentrated hydrochloric acid down in the gained resistates, stirred 10 minutes down in uniform temp subsequently.After reaction is finished, solution is transferred to pH12, transfer to pH7.4 with hydrochloric acid then, use chloroform (100ml * 5) extraction subsequently with aqueous sodium hydroxide solution.Organic layer is merged and use anhydrous sodium sulfate drying, steaming desolventizes then.After this, with gained resistates recrystallization in methyl alcohol-2-propyl alcohol, obtain the described title compound of 181mg (72%).Fusing point: 195-197 ℃ [α] _D ²⁵=-123.10, (c=0.515,1N aqueous sodium hydroxide solution) ¹H-NMR (400MHz, 0.1N NaOD) δ:

0.60(4H，s)，1.34-1.60(2H，m)，1.71-1.82(1H，m)，

1.99-2.07(1H，m)，2.20-2.29(1H，m)，3.46-3.65

(2H，m)，3.60(3H，s)，3.69-3.78(1H，m)，3.98-4.07

(1H，m)，4.93-4.96?and?5.12-5.15(1H，m)，7.60(1H，

d，J＝13.67Hz)，8.43(1H，d，J＝2.93Hz).

Ultimate analysis C ₂₁H ₂₃F ₂N ₃O ₄

Calculated value: C60.14 H5.53 N 10.02

Measured value: C60.02 H5.45 N 9.92 inventive embodiments 12:7-[(3R)-3-(the amino cyclopropyl of 1-)-1-pyrrolidyl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-carboxylic acid

With 322mg (0.89mmol) (3R)-1-carbobenzoxy-(Cbz)-3-(1-t-butoxycarbonyl amino cyclopropyl) tetramethyleneimine is dissolved in 10ml methyl alcohol, subsequently to wherein adding 100mg 5% palladium/carbon, carries out hydrogenation 2 hours at infrared lamp under the warm and normal pressure.After reaction is finished, filtering 5% palladium/carbon also steams and removes methyl alcohol, the gained resistates is dissolved in the 3ml tetramethylene sulfone, subsequently to wherein adding 0.124ml (0.89mmol) triethylamine and 172mg (0.5mmol) 6,7-two fluoro-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-carboxylic acid BF2 inner complex stirred 6 days under room temperature then.After reaction is finished, with reaction soln and 100ml ethyl acetate: ether=solution mixed in 1: 1, washed with 10% citric acid (100ml * 2), used dried over sodium sulfate then.After steaming desolventizes, the gained resistates is dissolved in the mixed solvent of 50ml methyl alcohol and 10ml water composition, solution is mixed reflux 4 hours with the 1ml triethylamine.After reaction is finished, steam to remove methyl alcohol and the gained resistates is mixed with the 100ml ether and wash with 10% citric acid (100ml * 2).The organic layer dried over mgso, and steaming desolventizes.The gained resistates carries out silica gel thin-layer chromatography (methyl alcohol: chloroform=1: 9), collect silica gel and use methyl alcohol: chloroform=solvent extraction in 1: 9.The ice bath cooling drips the 10ml concentrated hydrochloric acid down in the gained compound, stirred 30 minutes down in uniform temp subsequently.After reaction is finished, reaction soln is transferred to pH12, transfer to pH7.4 with hydrochloric acid then, use chloroform (100ml * 4) extraction subsequently with aqueous sodium hydroxide solution.Organic layer is merged and use anhydrous sodium sulfate drying, steaming desolventizes then.After this, with gained resistates recrystallization in the 2-propyl alcohol, obtain the described title compound of 81mg (40%).Fusing point: 195-197 ℃ [α] _D ²⁵=-320.00, (c=0.270,0.1N aqueous sodium hydroxide solution) ¹H-NMR (400 MHz, 0.1N NaOD) δ:

0.58(4H，s)，1.21-1.38(1H，m)，1.60-1.82(2H，m)，

2.01-2.07(1H，m)，2.22-2.32(1H，m)，2.53(3H，s)，

3.38-3.43(2H，m)，3.52-3.59(1H，m)，3.75-3.83

(1H，m)，4.10-4.14(1H，m)，4.93-4.96?and?5.09-

5.14(1H，m)，7.71(1H，d，J＝14.16Hz)，8.45(1H，d，

J＝2.44Hz).

Ultimate analysis C ₂₁H ₂₃F ₂N ₃O ₃

Calculated value: C62.52 H5.75 N10.42

Measured value: C62.48 H5.78 N10.25 inventive embodiments 13:7-[(3R)-3-(the amino cyclopropyl of 1-)-1-pyrrolidyl]-6-fluoro-1-[(R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid

With 322mg (0.89mmol) (3R)-1-carbobenzoxy-(Cbz)-3-(1-t-butoxycarbonyl amino cyclopropyl) tetramethyleneimine is dissolved in 10ml methyl alcohol, to wherein adding 100mg 5% palladium/carbon, carried out hydrogenation 2 hours under the warm normal pressure of infrared lamp subsequently.After reaction was finished, filtering 5% palladium/carbon also steamed and removes methyl alcohol, and the gained resistates is dissolved in the 5ml acetonitrile, subsequently to wherein adding 0.5ml triethylamine and 113mg (0.4mmol) 6,7-two fluoro-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid, reflux is 18 hours then.After reaction is finished, make the reaction soln naturally cooling, filter and collect the crystallization that is generated.Under the ice bath cooling, Dropwise 5 ml concentrated hydrochloric acid in the gained crystallization stirred 30 minutes down in uniform temp subsequently.After reaction is finished, reaction soln is transferred to pH12, transfer to pH7.4 with hydrochloric acid then, use chloroform (50ml * 3) extraction subsequently with aqueous sodium hydroxide solution.Organic layer is merged and use dried over sodium sulfate, steaming desolventizes then.After this, with gained resistates recrystallization in ammoniacal liquor-ethanol, obtain the described title compound of 120mg (77%).Fusing point: 240-242 ℃ [α] _D ²⁵=-32.30, (c=0.260,0.1N aqueous sodium hydroxide solution) ¹H-NMR (400 MHz, 0.1N NaOD) δ:

0.57(4H，s)，1.68-1.83(3H，m)，2.01-2.10(1H，m)，

2.19-2.25(1H，m)，3.29-3.35(1H，m)，3.48-3.65

(4H，m)，5.12-5.17and5.28-5.33(1H，m)，6.80(1H，

d，J＝7.32Hz)，7.76(1H，d，J＝15.13Hz)，8.39(1H，

s).

Ultimate analysis C ₂₀H ₂₁F ₂N ₃O ₃

Calculated value: C61.69 H5.44 N10.79

Measured value: C60.64 H5.27 N10.59 inventive embodiments 147-[(3R)-3-(the amino cyclopropyl of 1-)-1-pyrrolidyl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid

With 180mg (0.5mmol) (3R)-1-carbobenzoxy-(Cbz)-3-(1-t-butoxycarbonyl amino cyclopropyl) tetramethyleneimine is dissolved in 10ml methyl alcohol, to wherein adding 100mg 5% palladium/carbon, carried out hydrogenation 2 hours under the warm normal pressure of infrared lamp subsequently.After reaction is finished, filtering 5% palladium/carbon also steams and removes methyl alcohol, the gained resistates is dissolved in the 5ml acetonitrile, subsequently to wherein adding 0.5ml triethylamine and 144mg (0.48mmol) 7-chloro-6-fluoro-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, reflux is 1 hour then, then stirs 18 hours under room temperature.After reaction is finished, make the reaction soln naturally cooling, filter and collect the crystallization that is generated.Under the ice bath cooling, Dropwise 5 ml concentrated hydrochloric acid in the gained crystallization stirred 30 minutes down in uniform temp subsequently.After reaction is finished, reaction soln is transferred to pH12, transfer to pH7.4 with hydrochloric acid then, use chloroform (50ml * 3) extraction subsequently with aqueous sodium hydroxide solution.Organic layer is merged and use dried over sodium sulfate, steaming desolventizes then.After this, with gained resistates recrystallization in liquefied ammonia-ethanol, obtain the described title compound of 79mg (42%).Fusing point: 232-234 ℃ [α] _D ²⁵=58.33, (c=0.120,0.1N aqueous sodium hydroxide solution) ¹H-NMR (400 MHz, 0.1N NaOD) δ:

0.58(4H，s)，1.60-1.87(3H，m)，2.05-2.15(1H，m)，

2.20-2.31(1H，m)，3.48-3.79(3H，m)，3.95-4.07

(2H，m)，5.02-5.09and5.19-5.23(1H，m)，7.85(1H，

d，J＝13.19Hz)，8.37(1H，s).

Ultimate analysis C ₁₉H ₂₀F ₂N ₄O ₃

Calculated value: C58.46 H5.16 N14.35

Measured value: C59.39 H4.97 N14.27 inventive embodiments 15:7-[3-(the amino cyclobutyl of 1-)-1-pyrrolidyl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-carboxylic acid (cut 2)

Be dissolved in 6 in the 6ml tetramethylene sulfone to 446mg (1.30mmol), 7-two fluoro-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-carboxylic acid BF ₂Add 530mg (2.20mmol) 3-(1-t-butoxycarbonyl amino cyclobutyl) tetramethyleneimine (cut 2) and 0.54ml triethylamine in the inner complex, under room temperature, stirred 12 days subsequently.Steam except that behind the triethylamine, gained resistates and mixed being incorporated under the room temperature of 10ml water were stirred 30 minutes.The crystallization that is generated is washed with water, filter to collect, be dissolved in 20ml methyl alcohol then: in the mixed solvent of water=9: 1, solution was mixed also reflux 3 hours with the 4ml triethylamine.After steaming desolventizes, the gained resistates is mixed with the 50ml chloroform, wash and use dried over mgso with 10% citric acid (20ml * 2), steaming desolventizes then.In the gained resistates, add the 5ml concentrated hydrochloric acid and under room temperature, stirred 2 hours, then with reaction soln with chloroform (5ml * 2) washing.With 20% aqueous sodium hydroxide solution reaction soln is transferred to pH7.3 and uses chloroform (30ml * 3) extraction.Organic layer is merged and use dried over sodium sulfate, steaming desolventizes then.With described resistates through preparation TLC (low layer chloroform: methyl alcohol: water=7: 3: 1 launches) separate also purifying and in ethanol recrystallization, obtain the described title compound of 220mg (41%).Fusing point: 140-143 ℃ ¹H-NMR (400MHz, 0.1N NaOD) δ:

1.06-1.21(1H，m)，1.55-1.71(3H，m)，1.81-1.85

(3H，m)，1.91-2.08(3H，m)，2.33-2.48(4H，m)，3.17

-3.24(2H，m)，3.44-3.48(1H，m)，3.67-3.68(1H，

m)，4.02-4.05(1H，m)，7.64(1H，d，J＝14.16Hz)，

8.44 (1H, s) .[α] _D ²³=-318.47, (c=0.184, methyl alcohol/chloroform=2/1)

Ultimate analysis C ₁₉H ₁₉N ₄O ₃F ₃1/4H ₂O

Calculated value: C60.68 H6.25 N9.65

Measured value: C60.41 H6.20 N9.58 inventive embodiments 16:5-amino-6,8-two fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1, the 4-dihydro-7-[(3R)-(1-methylamino-cyclopropyl)-1-pyrrolidyl]-the 4-Oxoquinoline-3-carboxylic acid

With 310mg (0.83mmol) (3R)-the amino cyclopropyl of 1-carbobenzoxy-(Cbz)-3-[1-(N-tertbutyloxycarbonyl-N-methyl)] tetramethyleneimine is dissolved in 10ml methyl alcohol, subsequently to wherein adding 200mg 5% palladium/carbon, carries out hydrogenation 1 hour at infrared lamp under the warm and normal pressure.After reaction is finished, filtering 5% palladium/carbon also steams and removes methyl alcohol, the gained resistates is dissolved in the 10ml acetonitrile, subsequently to wherein adding 1.24ml1,8-diazabicyclo [5.4.0] 11-7-alkene (DBU) and 190mg (0.6mmol) 5-amino-6,7,8-three fluoro-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid, reflux is 18 hours then.After reaction is finished, steam except that acetonitrile and with the gained resistates and mix, wash with 10% citric acid (100ml * 1) with the 200ml chloroform.The organic layer dried over sodium sulfate, and steaming desolventizes.The gained resistates is carried out silica gel thin-layer chromatography (methyl alcohol: chloroform=5: 95), collect silica gel and use methyl alcohol: chloroform=solvent systems extraction in 1: 9 twice.Under the ice bath cooling, Dropwise 5 ml concentrated hydrochloric acid in the gained compound stirred 10 minutes subsequently.After reaction is finished, reaction soln is transferred to pH12, transfer to pH7.4 with hydrochloric acid then, use chloroform (50ml * 3) extraction subsequently with aqueous sodium hydroxide solution.Organic layer is merged and use dried over sodium sulfate, steaming desolventizes then.After this, with gained resistates recrystallization in liquefied ammonia-2-propyl alcohol, obtain the described title compound of 96mg (37%).Fusing point: 180-181 ℃ [α] _D ²⁵=-242.26, (c=0.265,0.1N aqueous sodium hydroxide solution) ¹H-NMR (400 MHz, 0.1N NaOD) δ:

0.54-0.65(4H，m)，1.37-1.64(3H，m)，1.88-1.98

(1H，m)，2.33(3H，s)，2.75-2.87(1H，m)，3.29-3.48

(1H，m)，3.51-3.64(2H，m)，3.71-3.83(2H，m)，4.80

-4.91and5.03-5.07(1H，m)，8.18(1H，s).

Ultimate analysis C ₂₁H ₂₃F ₂N ₄O ₃

Calculated value: C56.63 H5.43 N12.58

Measured value: C56.57 H5.31 N12.44 inventive embodiments 17:6-fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-7-[(3R)-3-(1-methylamino-cyclopropyl)-1-pyrrolidyl]-the 4-Oxoquinoline-3-carboxylic acid

With 449mg (1.2mmol) (3R)-the amino cyclopropyl of 1-carbobenzoxy-(Cbz)-3-[1-(N-tertbutyloxycarbonyl-N-methyl)] tetramethyleneimine is dissolved in 10ml methyl alcohol, subsequently to wherein adding 100mg 5% palladium/carbon, carries out hydrogenation 1 hour at infrared light under the warm and normal pressure.After reaction is finished, filtering 5% palladium/carbon also steams and removes methyl alcohol, the gained resistates is dissolved in the 10ml methyl-sulphoxide, subsequently to wherein adding 0.174ml (1.25mmol) triethylamine and 217mg (0.6mmol) 6,7-two fluoro-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-carboxylic acid BF ₂Inner complex stirred 5 hours under room temperature then.After reaction is finished, steam and remove methyl-sulphoxide, the gained resistates is mixed with water, filter and collect crystallization and water (10ml * 3) washing that is generated.The gained crystallization is dissolved in the mixed solvent that 20ml methyl alcohol and 5ml water constitutes, solution was mixed also reflux 15.5 hours with the 0.3ml triethylamine.After reaction is finished, steam to remove methyl alcohol, reaction soln is mixed with 50ml water and extract with chloroform (20ml * 2).Organic layer is merged, extract and use dried over sodium sulfate with 10% citric acid (100ml * 2), steaming desolventizes.Under ice-cooled, Dropwise 5 ml concentrated hydrochloric acid in the gained resistates stirred 10 minutes down in uniform temp subsequently.After reaction is finished, reaction soln is transferred to pH12, transfer to pH7.4 with hydrochloric acid then, use chloroform (50ml * 5) extraction subsequently with aqueous sodium hydroxide solution.Organic layer is merged and use dried over sodium sulfate, steaming desolventizes then.After this, with gained resistates recrystallization in methyl alcohol-ethanol, obtain the described title compound of 215mg (83%).Fusing point: 208-209 ℃ [α] _D ²⁵=-123.42, (c=0.525,0.1N aqueous sodium hydroxide solution) ¹H-NMR (400 MHz, 0.1N NaOD) δ:

0.53-0.69(4H，m)，1.32-1.59(3H，m)，1.91-2.02

(1H，m)，2.34(3H，s)，2.85-2.95(1H，m)，3.29-3.38

(1H，m)，3.51-3.62(2H，m)，3.57(3H，s)，3.70-3.79

(1H，m)，3.98-4.07(1H，m)，4.95-4.98and5.09-

5.13(1H，m)，7.66(1H，d，J＝14.23Hz)，8.39(1H，d，

J＝2.93).

Ultimate analysis C ₂₂H ₂₅F ₂N ₃O ₄

Calculated value: C60.96 H5.81 N9.69

Measured value: C60.79 H5.73 N9.55 inventive embodiments 18:6-fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-7-[(3R)-3-(1-methylamino-cyclopropyl)-1-pyrrolidyl]-the 4-Oxoquinoline-3-carboxylic acid

With 749mg (2.0mmol) (3R)-the amino cyclopropyl of 1-carbobenzoxy-(Cbz)-3-[1-(N-tertbutyloxycarbonyl-N-methyl)] tetramethyleneimine is dissolved in 10ml methyl alcohol, subsequently to wherein adding 200mg 5% palladium/carbon, carries out hydrogenation 1 hour at infrared light under the warm and normal pressure.After reaction is finished, filtering 5% palladium/carbon also steams and removes methyl alcohol, the gained resistates is dissolved in the 5ml tetramethylene sulfone, subsequently to wherein adding 0.279ml (2.0mmol) triethylamine and 345mg (1.0mmol) 6,7-two fluoro-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-carboxylic acid BF2 inner complex stirred 11 days under room temperature then.After reaction is finished, reaction soln is mixed with 50ml water, filter and collect crystallization and water (10ml * 2) washing that is generated.The gained crystallization is dissolved in 32ml methyl alcohol and the 8ml water, solution is mixed with the 0.5ml triethylamine and reflux 18 hours.After reaction is finished, steam to remove methyl alcohol, the gained resistates is mixed with the 200ml chloroform and wash with 10% citric acid (100ml * 1).Organic layer desolventizes with dried over sodium sulfate and steaming.The gained resistates is carried out silica gel thin-layer chromatography (methyl alcohol: chloroform-1: 9), collect silica gel and use methyl alcohol: chloroform=1: 9 mixed extractant solvent.Under ice-cooled, Dropwise 5 ml concentrated hydrochloric acid in the gained compound stirred 30 minutes down in uniform temp subsequently.After reaction is finished, reaction soln is transferred to pH12, transfer to pH7.4 with hydrochloric acid then, use chloroform (100ml * 3) extraction subsequently with aqueous sodium hydroxide solution.Organic layer is merged and use dried over sodium sulfate, steaming desolventizes then.After this, with gained resistates recrystallization in methyl alcohol-ethanol, obtain the described title compound of 124mg (30%).Fusing point: 211-212 ℃ [α] _D ²⁵=-330.18, (c=0.275, methyl alcohol) ¹H-NMR (400 MHz, 0.1N NaOD) δ:

0.51-0.67(4H，m)，1.20-1.35(1H，m)，1.43-1.68

(2H，m)，1.94-2.02(1H，m)，2.32(3H，s)，2.46(3H，

s)，2.89-2.98(1H，m)，3.30-3.42(3H，m)，3.75-

3.83(1H，m)，4.05-4.13(1H，m)，4.90-4.93and5.03

-5.10(1H，m)，7.66(1H，d，J＝14.65Hz)，8.41(1H，

d，J＝3.42Hz).

Ultimate analysis C ₂₂H ₂₅F ₂N ₃O ₃

Calculated value: C63.30 H6.04 N10.07

Measured value: C62.97 H6.25 N9.91 inventive embodiments 19:5-amino-7-[(3R)-and 3-(1-ethylamino cyclopropyl)-1-pyrrolidyl]-6,8-two fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid

With 414mg (1.07mmol) (3R)-the amino cyclopropyl of 1-carbobenzoxy-(Cbz)-3-[1-(N-tertbutyloxycarbonyl-N-ethyl)] tetramethyleneimine is dissolved in 15ml methyl alcohol, subsequently to wherein adding 200mg 5% palladium/carbon, carried out hydrogenation 1.5 hours under the warm and normal pressure at infrared light.After reaction is finished, filtering 5% palladium/carbon also steams and removes methyl alcohol, the gained resistates is dissolved in the 10ml acetonitrile, subsequently to wherein adding 1ml triethylamine and 225mg (0.71mmol) 5-amino-6,7,8-three fluoro-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid, reflux is 18 hours then.After reaction is finished, steam to remove acetonitrile, the gained resistates is mixed with the 100ml chloroform and wash with 10% citric acid (100ml * 1).The organic layer dried over sodium sulfate, steaming desolventizes.Under ice-cooled, Dropwise 5 ml concentrated hydrochloric acid in the gained resistates stirred 1 hour subsequently.After reaction is finished, reaction soln is mixed with 10ml water and wash with methylene dichloride (15ml * 1).With aqueous sodium hydroxide solution water layer is transferred to pH12, transfer to pH7.4 with hydrochloric acid then, use chloroform (50ml * 3) extraction subsequently.Organic layer is merged and use dried over sodium sulfate, steaming desolventizes then.After this, with gained resistates recrystallization in liquefied ammonia-2-propyl alcohol, obtain the described title compound of 243mg (76%).Fusing point: 151-152 ℃ [α] _D ²⁵=-116.82, (c=0.315,0.1N aqueous sodium hydroxide solution) ¹H-NMR (400 MHz, 0.1N NaOD) δ:

0.51-0.69(4H，m)，1.04(3H，t，J＝7.32Hz)，1.37-

1.62(3H，m)，1.92-1.99(1H，m)，2.71(2H，q，J＝

7.32Hz)，2.78-2.88(1H，m)，3.30-3.39(1H，m)，

3.53-3.64(2H，m)，3.72-3.85(2H，m)，4.85-4.92

and?5.03-5.07(1H，m)，8.19(1H，s).

Ultimate analysis C ₂₂H ₂₅F ₃N ₄O ₃1/4H ₂O

Calculated value: C58.08 H5.65 N12.31

Measured value: C58.23 H5.89 N11.98 inventive embodiments 20:5-amino-6,8-two fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1, the 4-dihydro-7-[(3R)-the amino cyclopropyl of 3-[1-(2-hydroxyethyl)]-the 1-pyrrolidyl]-the 4-Oxoquinoline-3-carboxylic acid

With 332mg (0.67mmol) (3R)-1-carbobenzoxy-(Cbz)-3-[1-[N-(2-benzyloxy ethyl)-N-tertbutyloxycarbonyl] amino cyclopropyl] tetramethyleneimine is dissolved in 20ml methyl alcohol, and is to wherein adding 100mg 5% palladium/carbon, warm down at infrared light subsequently, 7kg/cm ²Carry out hydrogenation 24 hours under the pressure.After reaction is finished, filtering 5% palladium/carbon also steams and removes methyl alcohol, the gained resistates is dissolved in the 10ml acetonitrile, subsequently to wherein adding 1ml triethylamine and 177mg (0.56mmol) 5-amino-6,7,8-three fluoro-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-4-dihydro-4-oxo quinoline-3-carboxylic acid, reflux is 23 hours then.After reaction is finished, steam to remove acetonitrile, the gained resistates is mixed with the 100ml chloroform and wash with 10% citric acid (100ml * 1).The organic layer dried over sodium sulfate, steaming desolventizes.The gained resistates carries out silica gel thin-layer chromatography (methyl alcohol: chloroform=1: 9), collect silica gel and use methyl alcohol: chloroform=solvent systems extraction in 1: 9.Under ice-cooled, in the gained compound, drip the 10ml concentrated hydrochloric acid, stirred subsequently 30 minutes.After reaction is finished, reaction soln is washed with methylene dichloride (10ml * 2).With aqueous sodium hydroxide solution water layer is transferred to pH12, transfer to pH7.4 with hydrochloric acid then, use chloroform (100ml * 3) extraction subsequently.Organic layer is merged and use dried over sodium sulfate, steaming desolventizes then.After this, with gained resistates recrystallization in liquefied ammonia-ethanol, obtain the described title compound of 97mg (36%).Fusing point: 198-200 ℃ [α] _D ^22.5=-141.49, (c=0.335,0.1N aqueous sodium hydroxide solution) ¹H-NMR (400 MHz, 0.1N NaOD) δ:

0.58-0.66(4H，m)，1.45-1.60(3H，m)，1.92-1.97

(1H，m)，2.82-2.88(3H，m)，3.31-3.38(1H，m)，3.55

-3.69(4H，m)，3.75-3.83(2H，m)，4.85-4.92and

5.03-5.08(1H，m)，8.19(1H，s).

Ultimate analysis C ₂₂H ₂₅F ₃N ₄O ₄1/4H ₂O

Calculated value: C56.11 H5.46 N11.90

Measured value: C56.38 H5.37 N11.75 inventive embodiments 21:6-fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1, the 4-dihydro-7-[(3R)-the amino cyclopropyl of 3-[1-(2-hydroxyethyl)]-the 1-pyrrolidyl]-8-methoxyl group-4-Oxoquinoline-3-carboxylic acid

With 210mg (0.78mmol) (3R)-the amino cyclopropyl of 3-[1-(2-hydroxyethyl)] tetramethyleneimine is dissolved in the 10ml methyl-sulphoxide, subsequently to wherein adding 0.109ml (0.78mmol) triethylamine and 231mg (0.64mmol) 6,7-two fluoro-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-carboxylic acid BF ₂Inner complex stirred 20 hours under room temperature then.After reaction is finished, steam and remove methyl-sulphoxide, the gained resistates is mixed with water, filter and collect crystallization and water (10ml * 2) washing that is generated.The gained crystallization is dissolved in 16ml methyl alcohol and the 4ml water, solution is mixed with the 1ml triethylamine and reflux 3 hours.After reaction is finished, steam to remove methyl alcohol and the gained resistates is mixed with the 100ml chloroform and wash with 10% citric acid (100ml * 2).The organic layer dried over sodium sulfate, steaming desolventizes.The gained resistates carries out silica gel thin-layer chromatography (methyl alcohol: chloroform=1: 9), collect silica gel and use methyl alcohol: chloroform=solvent systems extraction in 1: 9.Under ice-cooled, Dropwise 5 ml concentrated hydrochloric acid in the gained compound stirred 30 minutes down in uniform temp subsequently.After reaction is finished, reaction soln is washed with methylene dichloride (20ml * 1).With aqueous sodium hydroxide solution water layer is transferred to pH12, transfer to pH7.4 with hydrochloric acid then, use chloroform (50ml * 3) extraction subsequently.Organic layer is merged and use dried over sodium sulfate, steaming desolventizes then.After this, with gained resistates recrystallization in liquefied ammonia-2-propyl alcohol, obtain the described title compound of 120mg (40%).Fusing point: 153-155 ℃ [α] _D ^25.4=-106.66, (c=0.270,0.1N aqueous sodium hydroxide solution) ¹H-NMR (400MHz, 0.1N NaOD) δ:

0.55-0.67(4H，m)，1.33-1.43(1H，m)，1.48-1.62

(2H，m)，1.94-2.04(1H，m)，2.82-2.94(3H，m)，3.29

-3.36(1H，m)，3.51-3.61(2H，m)，3.57(3H，s)，3.66

(2H，t，J＝5.86Hz)，3.66-3.78(1H，m)，3.98-4.05

(1H，m)，4.91-4.95and5.07-5.11(1H，m)，7.65(1H，

d，J＝14.16Hz)，8.39(1H，d，J＝2.93Hz).

Ultimate analysis C ₂₃H ₂₇F ₂N ₃O ₅

Calculated value: C59.60 H5.87 N9.07

Measured value: C59.34 H6.03 N8.84 inventive embodiments 22:6-fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1, the 4-dihydro-7-[(3R)-the amino cyclopropyl of 3-[1-(2-hydroxyethyl)]-the 1-pyrrolidyl]-8-methyl-4-Oxoquinoline-3-carboxylic acid

With 203mg (0.74mmol) (3R)-the amino cyclopropyl of 3-[1-(2-hydroxyethyl)] tetramethyleneimine is dissolved in the 2ml tetramethylene sulfone, subsequently to wherein adding 0.082ml (0.6mmol) triethylamine and 206mg (0.6mmol) 6,7-two fluoro-[(1R, 2S)-2-fluorine cyclopropyl]-the 8-methyl isophthalic acid, 4-dihydro-4-Oxoquinoline-3-carboxylic acid BF2 inner complex stirred 7 days under room temperature then.After reaction is finished, reaction mixture is mixed with the 100ml chloroform and wash with 10% citric acid (100ml * 1).The organic layer dried over sodium sulfate, steaming desolventizes.The gained resistates is dissolved in 16ml methyl alcohol and the 4ml water, solution is mixed with the 1ml triethylamine and reflux 3 hours.After reaction is finished, steam except that methyl alcohol and with the gained resistates and mix, wash with 10% citric acid (100ml * 1) with the 100ml chloroform.Organic layer desolventizes with dried over sodium sulfate and steaming.The gained resistates carries out silica gel thin-layer chromatography (methyl alcohol: chloroform=1: 9), collect silica gel and use methyl alcohol: chloroform=solvent systems extraction in 1: 9.Under ice-cooled, in the gained compound, drip the 2ml concentrated hydrochloric acid, stirred 30 minutes down in uniform temp subsequently.After reaction is finished, reaction soln is washed with methylene dichloride (20ml * 1).With aqueous sodium hydroxide solution water layer is transferred to pH12, transfer to pH7.4 with hydrochloric acid then, use chloroform (50ml * 3) extraction subsequently.Organic layer is merged and use dried over sodium sulfate, steaming desolventizes then.After this, with gained resistates recrystallization in liquefied ammonia-ethanol, obtain the described title compound of 63mg (23%).Fusing point: 168-170 ℃ [α] _D ^25.2=-236.47, (c=0.170,0.1N aqueous sodium hydroxide solution) ¹H-NMR (400 MHz, 0.1N NaOD) δ:

0.55-0.67(4H，m)，1.18-1.25(1H，m)，1.42-1.69

(2H，m)，1.92-1.99(1H，m)，2.43(3H，s)，2.82-2.94

(3H，m)，3.22-3.34(3H，m)，3.65(2H，t，J＝5.86

Hz)，3.69-3.79(1H，m)，4.03-4.09(1H，m)，4.90-

4.95and5.07-5.11(1H，m)，7.65(1H，d，J＝14.16

Hz)，8.43(1H，d，J＝2.93Hz).

Ultimate analysis C ₂₃H ₂₇F ₂N ₃O ₄

Calculated value: C61.74 H6.08 N9.39

Measured value: C61.68 H6.19 N9.31 inventive embodiments 23:5-amino-7-[3-(the amino cyclobutyl of 1-)-1-pyrrolidyl]-6,8-two fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid (cut 1)

136mg (0.57mmol) 3-(1-t-butoxycarbonyl amino cyclopropyl) tetramethyleneimine (cut 1) is suspended in the 10.0ml acetonitrile, subsequently to wherein adding 120mg (0.38mmol) 5-amino-6,7,8-three fluoro-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid and 0.79ml (3.79mmol) triethylamine, reflux spends the night then.After steaming desolventizes, the gained resistates is mixed with chloroform, anhydrous sodium sulfate drying is used in water, 10% aqueous citric acid solution and saturated brine washing then successively, steams subsequently to desolventize.To wherein adding the 2ml concentrated hydrochloric acid, under room temperature, stirred 2 hours subsequently.Reaction soln is mixed with 10ml water,, neutralize with aqueous sodium hydroxide solution then with the chloroform washing.It is also used dried over sodium sulfate with chloroform extraction, and steaming desolventizes then.After this, with gained resistates recrystallization in the 2-propyl alcohol, obtain the described title compound of 29mg (15%) yellow solid shape.Fusing point: 181-183 ℃ (decomposition) ¹H-NMR (0.1N-NaOD) δ:

1.53-1.72(4H，m)，1.81-1.91(3H，m)，1.98-2.13

(3H，m)，2.25-2.33(1H，m)，3.42-3.60(3H，m)，3.68

-3.80(2H，m)，4.81-5.03(1H，m)，8.25(1H，s).

Ultimate analysis C ₂₁H ₂₃F ₃N ₄O ₃1/4H ₂O

Calculated value: C57.20 H5.37 N12.71

Measured value: C57.09 H5.34 N12.38 inventive embodiments 24:5-amino-7-[3-(the amino cyclobutyl of 1-)-1-pyrrolidyl]-6,8-two fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid (cut 2)

242mg (1.00mmol) 3-(1-t-butoxycarbonyl amino cyclopropyl) tetramethyleneimine (cut 2) is suspended in the 10.0ml acetonitrile, subsequently to wherein adding 212mg (0.67mmol) 5-amino-6,7,8-three fluoro-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid and 1.40ml (6.70mmol) triethylamine, reflux spends the night then.After steaming desolventizes, the gained resistates is mixed with chloroform, anhydrous sodium sulfate drying is used in water, 10% aqueous citric acid solution and saturated brine washing then successively, steams subsequently to desolventize.To wherein adding the 2ml concentrated hydrochloric acid, under room temperature, stirred 2 hours subsequently.Reaction soln is mixed with 10ml water,, neutralize with aqueous sodium hydroxide solution then with the chloroform washing.It is also used dried over sodium sulfate with chloroform extraction, and steaming desolventizes then.After this, with gained resistates recrystallization in ethanol-isopropyl ether, obtain the described title compound of 292mg (37%) yellow solid shape.Fusing point: 133-139 ℃ ¹H-NMR (0.1N-NaOD) δ:

1.46-1.68(4H，m)，1.81-1.86(3H，m)，1.94-1.99

(1H，m)，2.05-2.10(2H，m)，2.27-2.31(1H，m)，3.47

-3.54(3H，m)，3.67-3.71(2H，m)，3.86-5.02(1H，

m)，8.19(1H，s).

Ultimate analysis C ₂₁H ₂₃F ₃N ₄O ₃H ₂O

Calculated value: C55.50 H5.54 N12.33

Measured value: C55.76 H5.33 N11.85 inventive embodiments 25:7-[3-(the amino cyclobutyl of 1-)-1-pyrrolidyl]-6,8-two fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-carboxylic acid (cut 2)

215mg (0.89mmol) 3-(1-t-butoxycarbonyl amino cyclopropyl) tetramethyleneimine (cut 2) is suspended in the 2.0ml methyl-sulphoxide, subsequently to wherein adding 215mg (0.60mmol) 6,7,8-three fluoro-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid and 249 μ l (1.80mmol) triethylamines stir under room temperature then and spend the night.Steam except that behind the triethylamine, the gained resistates is mixed with water, filter and collect the precipitation that generates.It is dissolved in the 10ml90% methanol aqueous solution, and solution mixes with the 2ml triethylamine and reflux 2 hours.After steaming desolventizes, the gained resistates is mixed with chloroform, with 10% aqueous citric acid solution and saturated brine washing, use anhydrous sodium sulfate drying then successively, steaming subsequently desolventizes.To wherein adding the 2ml concentrated hydrochloric acid, under room temperature, stirred 2 hours subsequently.Reaction soln is mixed with 10ml water,, neutralize with aqueous sodium hydroxide solution then with the chloroform washing.It is also used dried over sodium sulfate with chloroform extraction, and steaming desolventizes then.After this, with gained resistates recrystallization in ethanol-isopropyl ether, obtain the described title compound of 71mg (27%) yellow solid shape.Fusing point: 123-139 ℃ ¹H-NMR (0.1N-NaOD) δ:

1.33-1.40(1H，m)，1.50-1.60(1H，m)，1.68-1.79

(2H，m)，1.86-1.88(3H，m)，2.03-2.07(1H，m)，2.14

(2H，brs)，2.40-2.49(1H，m)，3.50-3.52(3H，m)，

3.56(3H，s)，3.67-3.71(1H，m)，3.98-4.03(1H，m)，

7.66(1H，d，J＝14.6Hz)，8.42(1H，2s).

Ultimate analysis C ₂₂H ₂₅F ₂N ₃O ₄3/4H ₂O

Calculated value: C50.12 H5.98 N9.40

Measured value: C58.94 H5.70 N9.13 inventive embodiments 26:5-amino-7-[3-(the amino cyclopropyl of 1-)-1-azetidinyl]-6,8-two fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid

212mg (1.00mmol) 3-(1-t-butoxycarbonyl amino cyclopropyl) azetidine is suspended in the 10.0ml acetonitrile, subsequently to wherein adding 2 10mg (0.66mmol) 5-amino-6,7,8-three fluoro-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid and 0.92ml (6.60mmol) triethylamine, reflux is 22 hours then.After steaming desolventizes, the gained resistates is mixed with chloroform, anhydrous sodium sulfate drying is used in water, the washing of 10% aqueous citric acid solution then, steams subsequently to desolventize.To wherein adding the 2ml concentrated hydrochloric acid, under room temperature, stirred 2 hours subsequently.With reaction soln with aqueous sodium hydroxide solution neutralization and use chloroform extraction.Extraction liquid desolventizes with dried over sodium sulfate and steaming.After this, with the gained resistates through preparation TLC (low layer chloroform: methyl alcohol: water=7: 3: 1 launches) purifying, recrystallization in strong aqua-ethanol, water and ether wash successively then, obtain the described title compound of 108mg (40%) yellow solid shape.Fusing point: 188-191 ℃ of (decomposition) [α] _D ²⁵=36.44, (c=0.225,1N aqueous sodium hydroxide solution) ¹H-NMR (0.1 N-NaOD) δ:

0.58(4H，2s)，1.54-1.61(2H，m)，2.84-2.87(1H，

m)，3.78(1H，m)，3.99(2H，m)，4.32(2H，m)，8.1(1H，

s).

Ultimate analysis C ₁₉H ₁₉F ₃N ₄O ₃1/2H ₂O

Calculated value: C54.68 H4.83 N13.42

Measured value: C54.39 H4.74 N13.22 inventive embodiments 27:5-amino-7-[(3R)-3-(the amino cyclopropyl of 1-)-1-pyrrolidyl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-carboxylic acid

With 649mg (1.8mmol) (3R)-1-carbobenzoxy-(Cbz)-3-(1-t-butoxycarbonyl amino cyclopropyl) tetramethyleneimine is dissolved in 20ml methyl alcohol, subsequently to wherein adding 200mg 5% (v/v) palladium/carbon, carries out hydrogenation 2 hours at infrared lamp under the warm and normal pressure.After reaction is finished, filtering 5% (v/v) palladium/carbon also steams and removes methyl alcohol, with the gained resistates is dissolved in the 20ml methyl-sulphoxide, subsequently to wherein adding 2ml triethylamine and 312mg (1mmol) 5-amino-6,7-two fluoro-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-8-methyl-4-Oxoquinoline-3-carboxylic acid stirred 18 hours down in 150 ℃ then.After reaction is finished, steam and remove methyl-sulphoxide, and the gained resistates is mixed with the 100ml chloroform, with 10% citric acid (100ml * 1) and saturated brine (100ml * 1) washing.The organic layer anhydrous sodium sulfate drying, and steaming desolventizes.Under ice-cooled, in the gained resistates, drip the 10ml concentrated hydrochloric acid, under room temperature, stirred 1 hour subsequently.After reaction was finished, reaction soln washed with methylene dichloride (20ml * 1), and water layer transfers to pH12 with aqueous sodium hydroxide solution, transfers to pH7.4 with hydrochloric acid then, used chloroform (100ml * 4) extraction subsequently.Organic layer is merged and use anhydrous sodium sulfate drying, steaming desolventizes then.The gained resistates is carried out silica gel thin-layer chromatography, low layer chloroform: methyl alcohol: after water=mixed solvent system launched in 7: 3: 1, extract with same solvent.After this, with gained crude product recrystallization in chloroform-isopropyl ether, obtain the described title compound of 101.5mg (24%).Fusing point: 215-216 ℃ [α] _D ²⁵=-406.96, (c=0.115,0.1 N aqueous sodium hydroxide solution) ¹H-NMR (400MHz, 0.1N-NaOD) δ:

0.55(4H，s)，1.09-1.18(1H，m)，1.45-1.57(1H，m)，

1.61-1.74(1H，m)，1.95-2.05(1H，m)，2.16-2.25

(1H，m)，2.27(3H，s)，3.24-3.37(2H，m)，3.45-3.57

(1H，m)，3.68-3.80(1H，m)，3.89-3.98(1H，m)，4.85

-4.91and5.02-5.07(1H，m)，8.26(1H，d，J＝2.93

Hz).

Ultimate analysis C ₂₁H ₂₄F ₂N ₄O ₃1/2H ₂O

Calculated value: C59.01 H5.89 N13.39

Measured value: C59.35 H5.85 N12.83 inventive embodiments 28:7-[(3R)-3-(the amino cyclopropyl of 1-)-1-pyrrolidyl]-6,8-two fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-5-hydroxyl-4-Oxoquinoline-3-carboxylic acid

With 360mg (1.00mmol) (R)-1-carbobenzoxy-(Cbz)-3-(1-tertbutyloxycarbonyl aminomethyl cyclopropyl) tetramethyleneimine is dissolved in 10ml methyl alcohol, to wherein adding 125mg 5% (v/v) palladium/carbon, under the room temperature hydrogen stream, stirred 3.5 hours subsequently.Behind diatomite filtration, steam and remove methyl alcohol.Gained resistates and 1ml triethylamine and 159mg (0.50mmol) are dissolved in 6,7 in the 10ml acetonitrile, 8-three fluoro-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-5-hydroxyl-4-Oxoquinoline-3-carboxylic acid mixed, with prepared mixture reflux 1 hour.After reaction was finished, reaction soln mixed with 10% citric acid and extracts with chloroform (50ml * 3).The organic layer anhydrous sodium sulfate drying, and steaming desolventizes.Dropwise 5 ml concentrated hydrochloric acid in the gained resistates stirred 1.5 hours under room temperature subsequently.After reaction was finished, reaction soln transferred to pH12 with aqueous sodium hydroxide solution, transfers to pH7.4 with hydrochloric acid then, filtered and collected out the crystallization that is settled out.Gained filtrate desolventizes organic layer with chloroform (100ml * 3) extraction with anhydrous sodium sulfate drying and steaming.After this, with the gained resistates and collected crystallization merges and in ethanol-liquefied ammonia recrystallization, obtain the described title compound of 227mg (82%).Fusing point: 199-201 ℃

¹H-NMR(400?MHz，0.1N?NaOD)δ：

0.55(4H，s)，1.76-0.64(3H，m)，2.05-1.94(1H，m)，

2.27-2.14(1H，m)，3.58-3.38(3H，m)，3.76-3.65

(1H，m)，3.87-3.76(1H，m)，5.07-4.81(1H，m)，8.12

(1H, s) .[α] _D ²¹=-159.33, (c=0.625,0.1 N aqueous sodium hydroxide solution)

Ultimate analysis C ₂₀H ₂₀F ₃N ₃O ₄1/3C ₂H ₅OH3/4H ₂O

Calculated value: C54.89 H5.24 N9.29

Measured value: C54.94 H5.35 N9.32 inventive embodiments 29:5-amino-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-7-[3-(R)-(1-methylamino-cyclopropyl)-1-pyrrolidyl]-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid hydrochloride

To 1-carbobenzoxy-(Cbz)-3-(R)-[1-(N-tertbutyloxycarbonyl-N-methyl) amino-cyclopropyl] tetramethyleneimine (1.015g, add in 2.710mmol) 5% palladium/activated carbon catalyst (water content 55.6%, 1.0g).Is 4.5kg/cm with mixture in initial hydrogen-pressure ²With stirring under the room temperature 3 hours, use ethanol through diatomite filtration then, remove catalyzer.With the filtrate vacuum concentration, in methyl-sulphoxide (7.5ml) solution of the unformed resistates of gained, add triethylamine (3.8ml) and 5-amino-6,8-two fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid (351.1mg, 1.124mmol), under the nitrogen atmosphere mixture was stirred 15 hours down in 150 ℃.After the cooling,, remove methyl-sulphoxide, be dissolved in chloroform (100ml) gained mixture vacuum concentration.Solution is used anhydrous magnesium sulfate drying, subsequently vacuum concentration with 10% citric acid (100ml) and saturated sodium-chloride water solution (100ml) washing.Under 0 ℃, Dropwise 35 % hydrochloric acid (10ml) in the gained resistates, mixture stirred under room temperature 1 hour, used methylene dichloride (50ml * 2) washing then.Water layer transfers to pH7.4 with the 1N sodium hydroxide solution, uses chloroform (100ml * 4) extraction subsequently.With the organic layer anhydrous magnesium sulfate drying that merges, vacuum concentration then.With gained resistates 2-propyl alcohol-isopropyl ether recrystallization purifying.Under 0 ℃, in the sedimentary ethanol of gained (20ml) solution, add 1N hydrochloric acid (2.0ml), mixture stirred 5 minutes down in 0 ℃, and vacuum concentration is to doing then.Add ether in resistates after, the gained precipitation is with 2-propyl alcohol-ethyl alcohol recrystallization purifying, under 80 ℃ of vacuum dry 37 hours then, obtains the required product of pale yellow powder shape (288.3mg, 54.7%).Fusing point: 196.3-198.6 ℃ of (decomposition) [α] _D ^22.8=-620.95 ° of (c=0.422, H ₂O) ¹H-NMR (400 MHz, D ₂O) δ:

8.51(1H，d，J＝3.51Hz)，5.02and4.91(1H，m)，4.03

-3.83(1H，m)，3.60-3.41(2H，m)，3.39-3.21(1H，

m)，2.93-2.83(1H，m)，2.81(3H，s)，2.21(3H，s)，

2.17-2.11(1H，m)，1.83-1.61(3H，m)，1.59-1.39

(1H，m)，1.19-1.09(1H，m)，0.64-0.59(4H，m).

Ultimate analysis C ₂₂H ₂₆F ₂N ₄O ₃HCl

Calculated value: C53.27; H6.08; N11.30

Measured value: C53.19; N6.11; N11.21 reference example J-1:4-(1,1-diethoxy carbonyl ethyl)-3,5,6-trifluoro-phthalic acid dimethyl ester

Under ice-cooled, (34.84g, (8.0g is in DMF 0.20mol) (300ml) suspension 0.20mol) to join 80%NaH with dimethyl malonate.(53.23g 0.20mol) and with mixture stirred under room temperature 24 hours to add ptfe dimethyl phthalate in mixture.(evaporation obtains the described title compound of the faint yellow oily of 83.7g to reaction mixture for 3 * 500ml) washings, anhydrous sodium sulfate drying with ethyl acetate (1000ml) dilution, solution with water. ¹H-NMR(400?MHz，D ₂O)δ：

1.27(6H，t，J＝7Hz)，1.85(3H，s)，3.91(3H，s)，

3.97(3H，s)，4.26(2H，q，J＝7Hz)，4.27(2H，q，J＝

7Hz). reference example J-2:4-(1-carboxy ethyl)-3,5,6-trifluoro-phthalic acid

With 4-(1,1-diethoxy carbonyl ethyl)-3,5, and 6-trifluoro-phthalic acid dimethyl ester (12.9g, 30.7mmol), the mixture of hydrochloric acid (120ml) and acetate (120ml) refluxed 24 hours.Reaction mixture is concentrated into dried, obtains the described title compound of 9.0g colourless crystallization shape. ¹H-NMR(400?Mhz，D ₂O)δ：

1.45 (3H, d, J=7.4Hz), 4.25-4.32 (2H, m). reference example J-3:3-ethyl-2,4,5-trifluoro-benzoic acid

With 4-(1-carboxy ethyl)-3,5, (14.9g 47.9mmol), the mixture of methyl-sulphoxide (100ml) and triethylamine (30ml) is in 140 ℃ of heating 4 days down, and is concentrated into reaction mixture dried the 6-trifluoro-phthalic acid.In resistates, add 1N HCl (100ml), solution extracted with diethyl ether.Extraction liquid salt water washing, anhydrous sodium sulfate drying, evaporation obtains the described title compound of the faint yellow crystalloid of 9.27g then. ¹H-NMR(400?MHz，CDCl ₃)δ：

1.24(3H，7，J＝7Hz)，2.78(2H，q，J＝7Hz)，7.67-

7.73 (1H, m), 8.5-9.3 (1H, broad). reference example K-1:5-amino-1-[(2S)-fluoro-(1R)-cyclopropyl]-1,4-three hydrogen-8-methoxyl group-4-Oxoquinoline-3-carboxylic acid ethyl ester

With 1-[(2S)-fluoro-(1R)-cyclopropyl]-1,4-dihydro-8-methoxyl group-5-nitro-4-Oxoquinoline-3-carboxylic acid ethyl ester (1.72g, 4.45mmol) be dissolved in the mixed solvent of THF (40ml) and EtOH (40ml), in solution, add Raney nickel (1ml) and mixture was stirred under room temperature under the nitrogen atmosphere 1.5 hours.Filtering Raney nickel and steaming desolventize, and resistates through silica gel chromatography, is used 3%MeOH-CHCl ₃Wash-out obtains the described title compound of 1.33g (84%). ¹H-NMR(400?MHz，CDCl ₃)：δ

1.39(3H，t，J＝6.84Hz)，1.40-1.60(2H，m)，3.76-

3.82(1H，m)，3.86(3H，s)，4.38(2H，q，J＝6.84Hz)，

4.72-4.76(0.5H，m)，4.88-4.92(0.5H，m)，8.40(1H，

S) reference example K-25-amino-1-[(2S)-fluoro-(1R)-cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-carboxylic acid

With 5-amino-1-[(2S)-fluoro-(1R)-cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-carboxylic acid ethyl ester (1.33g, 3.73mmol) be suspended in the mixed solvent of EtOH (10ml) and MeOH (5ml), in suspension, add 1N NaOH (8ml) and mixture was stirred under room temperature 2.5 hours.Steaming desolventizes, and is ice-cooled following, adds concentrated hydrochloric acid in resistates, and crystallization water that is settled out and EtOH washing obtain the described title compound of 1.0g (82%).Inventive embodiments 30:5-amino-7-(1-amino-3--azabicyclo [3.1.0] oneself-3-yl)-6-fluoro-1-[(2S)-and fluoro-(1R)-cyclopropyl]-1,4-dihydro-8-methoxyl group-4-Oxoquinoline-3-carboxylic acid

With 1-t-butoxycarbonyl amino-3-azabicyclo [3.1.0] hexane (cut 1) (350mg, 1.77mmol) and triethylamine (2ml) join 5-amino-6,7-two fluoro-1-[(2S)-and fluoro-(1R)-cyclopropyl]-1, (335mg is in DMSO 1.02mmol) (8ml) solution for 4-dihydro-8-methoxyl group-4-Oxoquinoline-3-carboxylic acid.Mixture heated 24 hours down in 100 ℃, and steaming desolventizes.In resistates, add CHCl ₃(20ml) and the filtering insolubles.Filtrate is washed with 10% citric acid solution (10ml * 2), anhydrous sodium sulfate drying, and steaming desolventizes then.Add concentrated hydrochloric acid (5ml) in resistates, mixture stirred under room temperature 5 minutes.Reaction mixture CHCl ₃(10ml * 2) washing, water layer is neutralized to pH 7.3 with the 20%NaOH aqueous solution, and uses CHCl ₃(30ml * 3) extraction.The anhydrous MgSO of extraction liquid ₄Dry and steaming desolventizes, and obtains 240mg (58%) crude product.With crude product in EtOH-28%NH ₃The solution weight crystallization obtains the described title compound of 120mg.Fusing point: 219-230 ℃ (decomposition) ¹H-NMR (400 MHz, 0.1N-NaOD): δ

0.62-0.65(1H，m)，0.78-0.82(1H，m)，1.21-1.52

(3H，m)，3.37(3H，s)，3.42(1H，d，J＝9.28Hz)，3.52

(2H，brs)，3.63-3.69(1H，m)，3.83-3.90(1H，m)，

4.75-4.81(0.5H，m)，4.90-4.95(0.5H，m)，8.26(1H，

S). inventive embodiments 31:5-amino-7-[(3R, 1 ' S)-3-(1-methylamino-ethyl)-1-pyrrolidyl]-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1.4-dihydro-8-methyl-4-Oxoquinoline-3-carboxylic acid

With (3R, 1 ' S)-3-[1-(N-methyl)-t-butoxycarbonyl amino ethyl] tetramethyleneimine (369mg), 5-amino-1-[(1R, 2S)-(2-fluorine cyclopropyl]-6,7-two fluoro-1,4-dihydro-8-methyl-4-Oxoquinoline-3-carboxylic acid (312mg), DMSO (5ml) and triethylamine (5ml) mix.Mixture stirred 3 days under 120 ℃ of nitrogen atmosphere, and steaming desolventizes.In resistates, add concentrated hydrochloric acid (5ml), mixture was stirred 30 minutes.Water layer transfers to pH11 with NaOH solution, transfers to pH 7.40 and uses CHCl with 1N HCl then ₃(500ml * 3) extraction.Extraction liquid desolventizes with anhydrous sodium sulfate drying and steaming.With resistates recrystallization in Virahol, obtain the described title compound of 125mg.

Ultimate analysis C ₂₁H ₂₆F ₂N ₄O ₃1/4H ₂O

Calculated value: C59.35 H6.29 N13.18

Measured value: C59.41 H6.21 N12.95

Industrial applicibility

Heterocyclic compound of the present invention has antibacterial activity to various types of bacteriums, therefore can be used as anti-The bacterium medicine.

Table 1 bacterium/compound (embodiment number) 1238 bacillus colis, NIHJ≤0.003≤0.003≤0.003≤0.003 shigella flexneri, 2A 5503≤0.003≤0.003≤0.003≤0.003 proteus vulgaris, 08,601 0.013≤0.003≤0.003 0.025 proteus mirabilis, IFO-3849 0.025 0.013 0.013 0.05 serratia marcescens, 10,100 0.05 0.025 0.025 0.10 pseudomonas aeruginosas, 32,104 0.05 0.05 0.10 0.10 pseudomonas aeruginosas, 32,121 0.025 0.10 0.025 0.05 Pseudomonas Maltophilias, IID-1275 0.025 0.05 0.05 0.10 staphylococcus aureus, 209P≤0.003≤0.003 0.006≤0.003 MRSE, 56,500 0.013 0.013 0.025 0.006 streptococcus pyogenes, G-36 0.05 0.013 0.05≤0.003 streptococcus fecalis, ATCC-19433 0.05 0.05 0.10 0.025 staphylococcus aureus, 87,037 0.10 0.10 0.20 0.05

Table 1 (continuing) bacterium/compound (embodiment number 9 10 16 23 bacillus colis, NIHJ 0.006≤0.003≤0.003≤0.003 shigella flexneri, 2A 5,503 0.006≤0.003≤0.003≤0.003 proteus vulgaris, 08,601 0.013 0.006≤0.003 0.013 proteus mirabilis, IFO-3849 0.10 0.006 0.013 0.025 serratia marcescens, 10,100 0.10 0.025 0.05 0.05 pseudomonas aeruginosas, 32,104 0.10 0.05 0.05 0.10 pseudomonas aeruginosas, 32,121 0.05 0.025 0.05 0.025 Pseudomonas Maltophilias, IID-1275 0.20 0.006 0.05 0.10 staphylococcus aureus, 209P≤0.003≤0.003≤0.003≤0.003 MRSE, 56500≤0.003≤0.003≤0.003≤0.003 streptococcus pyogenes, G-36≤0.003≤0.003≤0.003≤0.003 streptococcus fecalis, ATCC-19433 0.025 0.013 0.025 0.013 staphylococcus aureus, 87,037 0.025 0.006 0.025 0.006

Table 1 (continuing) bacterium/compound (embodiment number) 28 Ofloxacin bacillus colis, NIHJ≤0.003 0.025 shigella flexneri, 2A 5503≤0.003 0.05 proteus vulgaris, 08,601 0.006 0.025 proteus mirabilis, IFO-3849 0.013 0.10 serratia marcescens, 10,100 0.025 0.10 pseudomonas aeruginosas, 32,104 0.10 0.39 pseudomonas aeruginosas, 32,121 0.025 0.20 Pseudomonas Maltophilias, IID-1275 0.006 0.39 staphylococcus aureus, 209P≤0.003 0.20 MRSE, 56500≤0.003 0.78 streptococcus pyogenes, G-36≤0.003 1.56 streptococcus fecalis, ATCC-19433 0.013 1.56 staphylococcus aureus, 87,037 0.006＞6.25

Claims (7)

1. the N of a following formula (I) expression ₁Pyridone carboxylic acid derivatives or its salt of-(halogenated cyclopropyl)-replacement:

X wherein ¹Expression halogen atom or hydrogen atom;

X ²The expression halogen atom;

R ¹Expression hydrogen atom, hydroxyl, sulfydryl, halogenated methyl, amino, contain the alkyl of 1-6 carbon atom or contain the alkoxyl group of 1-6 carbon atom, wherein said amino can contain and is selected from formyl radical, contains the alkyl of 1-6 carbon atom and contains the substituting group of the acyl group of 2-5 carbon atom, condition is when described substituting group is alkyl, wherein alkyl can be same to each other or different to each other, and then described amino can be by dialkyl group-replacement;

R ²Be group shown in the following formula (II): R wherein ³And R ⁴Represent hydrogen atom independently or contain the alkyl of 1-6 carbon atom, and n is 1 or 2 integer; A represents the part-structure of nitrogen-atoms or following formula (III):

X wherein ³Expression hydrogen atom, halogen atom, cyano group, amino, the alkyl that contains 1-6 carbon atom, halogenated methyl, the alkoxyl group that contains 1-6 carbon atom or halogenated methoxy, wherein said amino can contain and is selected from formyl radical, contains the alkyl of 1-6 carbon atom and contains the substituting group of the acyl group of 2-5 carbon atom, condition is when described substituting group is alkyl, wherein alkyl can be same to each other or different to each other, and then described amino can be by dialkyl group-replacement; With

R represents hydrogen atom, phenyl, acetoxy-methyl, oxy acid methyl neopentyl, ethoxycarbonyl, choline base, dimethyl aminoethyl, 5-indanyl, 2-benzo [c] furanone alkynyl (phthalidynyl), 5-alkyl-2-oxo-1,3-dioxole-4-ylmethyl, 3-acetoxyl group-2-oxo butyl, contain 1-6 carbon atom alkyl, contain the alkoxy methyl of 2-7 carbon atom or the phenylalkyl that constitutes by alkylidene group that contains 1-6 carbon atom and phenyl.

2. according to the compound or its salt of claim 1, halogenated cyclopropyl is 1 described in its Chinese style (I), 2-is suitable-and the 2-halogenated cyclopropyl.

3. according to the compound or its salt of claim 2, R in its Chinese style (I) ²It is the pure substituting group of stereochemistry.

4. according to claim 1,2 or 3 compound or its salt, halogenated cyclopropyl described in its Chinese style (I) is the pure substituting group of stereochemistry.

5. according to the compound or its salt of claim 4, wherein said halogenated cyclopropyl be (1R, 2S)-the 2-halogenated cyclopropyl.

6. according to the compound or its salt of claim 5, X wherein ²It is fluorine atom.

7. antimicrobial compound, wherein said composition contains above-mentioned formula (I) compound or its salt and the pharmaceutically useful carrier as activeconstituents.