CN1019012B - Process for producing 1-substituted aryl-1, 4-dihydro-4-oxonaphthyridine derivative intermediates - Google Patents

Abstract

This invention relates to a process for industrially producing a 1-substituted aryl-1,4-dihydro-4-oxonaphthyridine derivative and a salt thereof which are useful as an antibacterial agent, and also to intermediates therefor and processes for producing the intermediates.

Description

Process for producing 1-substituted Aryl-1, 4-Dihydro-4-oxonaphthyridine derivative intermediates

The invention relates to the aryl-1 of chemical formula, 4-dihydro-4-oxo-1, the preparation method of 8-naphthyridines derivatives or its salt for the 1-replacement of (I-I)

R wherein ¹Represent hydrogen atom or carboxyl-protecting group; R ^2aRepresent 3-amino-1-pyrrolidyl, wherein amino can be protected, R ^2aOr the 1-piperazinyl, wherein imido grpup can be protected; X represents hydrogen atom or fluorine atom, and said derivative has very strong anti-microbial activity for gram positive bacterium and gram negative bacterium; The invention still further relates to the method for intermediate and these intermediates of preparation of this derivative of preparation.

Outline and summary 102-104 page or leaf and Japanese Patent Application Publication (Laid-Open) No 228 in the 24th international chemotherapy and antimicrobial agents meeting, in 479/85, all announced the aryl-1 of chemical formula for the 1-replacement of (I-I), 4-dihydro-4-oxo-1,8-naphthyridines derivatives and salt pair gram positive bacterium thereof and gram negative bacterium have very strong anti-microbial activity, oral or non-when the stomach and intestine administration, the Plasma Concentration height, and have such as remarkable character such as high securities.

The present invention relates to the compound of the logical formula I of following preparation and the method for its esters and their intermediate of preparation, also relate to formula II, the intermediate of (I-3) and (V)

Logical above formula I, (I b), (I-2), (I-3), (II-1), (II), (III), (IV), (V), (V a), (V-1), in (VI) and (VII), R ^1aThe representation carboxy protecting group; R ²Represent halogen atom, hydroxyl, azido-; any alkoxyl group that replaces, alkylthio, arylthio; alkyl sulfinyl, fragrant sulfinyl, alkane alkylsulfonyl; arylsulfonyl, alkane sulfonyloxy, arylsulfonyloxy; dialkoxy phosphorus acyloxy or two fragrant oxygen phosphoryls; 3-amino-1-pyrrolidyl, wherein amino can be protected, R ²Or the 1-piperazinyl, wherein imido grpup can be protected; R ^2bRepresentation hydroxy or the alkoxyl group that replaces arbitrarily, alkane alkylsulfonyl, arylsulfonyl, alkane sulfonyloxy, arylsulfonyloxy, dialkoxy phosphorus acyloxy or two fragrant oxygen phosphorus acyloxy; R ^2cThe arylthio of representing azido-or replacing arbitrarily, alkyl sulfinyl, fragrant sulfinyl, alkane alkylsulfonyl, arylsulfonyl, alkane sulfonyloxy, arylsulfonyloxy, dialkoxy phosphorus acyloxy or two fragrant oxygen phosphorus acyloxy; R ^2dRepresentation hydroxy, azido-, or the alkoxyl group that replaces arbitrarily, alkylthio, arylthio, alkyl sulfinyl, fragrant sulfinyl, alkane alkylsulfonyl, arylsulfonyl, alkane sulfonyloxy, arylsulfonyloxy, dialkoxy phosphorus acyloxy or two fragrant oxygen phosphorus acyloxy; R ³And R ⁴Can be identical or different groups, they represent alkyl or cycloalkyl, or R ³And R ⁴Connect to alkylidene group, this alkylidene group Base circlewise.R ⁵And R ⁶Can be identical or different groups, they be represented alkyl or form heterocycle with the nitrogen-atoms that is close to.Y represents halogen atom, and Z represents removable group, can be halogen atom, hydroxyl or the acyloxy that replaces arbitrarily, alkane sulfonyloxy, arylsulfonyloxy, dialkoxy phosphorus acyloxy or two fragrant oxygen phosphorus acyloxy; R ¹, R ^2aWith the implication of X as mentioned above.

The preparation approach of above-mentioned preparation method and intermediate is as follows, and this method can make the compound or its salt class of formula (I-1) in industrial preparation easily.

In above-mentioned production approach, R ⁹The O-representative is at R ²In the same alkoxyl group mentioned; R ¹⁰SO ³-representative is at R ²In same alkane sulfonyloxy or the arylsulfonyloxy mentioned; R ¹⁰The S-representative is at R ²In same alkylthio or the arylthio mentioned; R ¹⁰The SO-representative is at R ²In same alkyl sulfinyl or the fragrant sulfinyl mentioned; R ¹⁰SO ₂-representative is at R ²In same alkane alkylsulfonyl or the arylsulfonyl mentioned; (R ¹⁰O) ₂

Representative is at R ²In same dialkoxy phosphorus acyloxy or the two fragrant oxygen phosphorus acyloxy mentioned; R ⁹And R ¹⁰Each group can be at least by a R ²In the substituting group mentioned replace R ¹, R ^1a, R ^2a, X, the implication of Y and Z is as mentioned above.

Purpose of the present invention provides the aryl-1 that the 1-of preparation formula (I-1) replaces, 4-dihydro-4-oxo-1, and the commercial run easily of 8-naphthyridines derivatives and salt thereof, these compounds are useful antiseptic-germicides.

Another object of the present invention provides the aryl-1 into the 1-replacement of preparation formula (I-1), 4-dihydro-4-oxo-1, the intermediate of 8-naphthyridines derivatives or its salt.

Another object of the present invention provides the commercial run easily for preparing these intermediates.

The present invention is explained as follows in detail

In this manual, R ¹And R ^1aThe carboxyl-protecting group of representative comprises those groups that this field is commonly used, Japanese Patent Application Publication (Laid-Open) NO.80 for example, and the carboxyl-protecting group of mentioning in 665/84, as alkyl, benzyl, new penta oxygen methyl and three silyls etc.

R ², the halogen atom of Y and Z representative comprises for example fluorine, chlorine, bromine, iodine.R ²The alkoxyl group of representative comprises for example C _1-12Alkoxyl group, as methoxyl group, oxyethyl group, positive propoxy, isobutoxy, pentyloxy, hexyloxy, heptan the oxygen base, octyloxy, dodecyloxy etc.; R ²The alkylthio of representative comprises, C for example _1-12Alkylthio, as methylthio group, ethylmercapto group, positive rosickyite base, the iprotiazem base, the isobutyl sulfenyl, uncle's butylthio, penta sulfenyl, own sulfenyl, heptan sulfenyl, hot sulfenyl, dodecane sulfenyl etc.; Arylthio comprises, thiophenyl for example, naphthalene sulfenyl etc.; R ²The alkyl sulfinyl of representative comprises, C for example _1-5Alkyl sulfinyl, as methanesulfinyl, second sulfinyl etc.; The virtue sulfinyl comprises for example benzenesulfinyl and naphthalene sulfinyl etc.; R ²The alkane alkylsulfonyl of representative comprises, C for example _1-5The alkane alkylsulfonyl is as methylsulfonyl and ethylsulfonyl etc.; R ²The arylsulfonyl of representative comprises, for example benzenesulfonyl and naphthalene sulfonyl base etc.; R ²The alkane sulfonyloxy of representative comprises, C for example _1-5The alkane sulfonyloxy is as mesyloxy and ethanesulfonyloxy group etc.; R ²The arylsulfonyloxy of representative comprises phenylsulfonyloxy and naphthalene sulfonyl oxygen base etc.; R ²The dialkoxy phosphorus acyloxy of representative comprises, two-C for example _1-5Alcoxyl phosphorus acyloxy, as dimethoxy phosphorus acyloxy, diethoxy phosphorus acyloxy, dipropyl oxygen phosphorus acyloxy, two fourth oxygen phosphorus acyloxy etc.; R ²Two fragrant oxygen phosphorus acyloxy of representative comprise, for example hexichol oxygen phosphorus acyloxy etc.

Above-mentioned R ²The alkoxyl group of representative, alkylthio, arylthio, alkyl sulfinyl, the virtue sulfinyl, alkane alkylsulfonyl, arylsulfonyl, the alkane sulfonyloxy, arylsulfonyloxy, dialkoxy phosphorus acyloxy and two fragrant oxygen phosphorus acyloxy can be replaced by a following substituting group at least: halogen atom such as fluorine, chlorine, bromine, iodine etc.; Nitro; Low alkyl such as methyl, ethyl, n-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl etc.; Low-alkoxy such as methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert.-butoxy etc.; Or the like.

R ^2bThe alkoxyl group of representative, alkane alkylsulfonyl, arylsulfonyl, alkane sulfonyloxy, arylsulfonyloxy, dialkoxy phosphorus acyloxy and two fragrant oxygen phosphorus acyloxy; R ^2cThe arylthio of representative, alkyl sulfinyl, fragrant sulfinyl, alkane alkylsulfonyl, arylsulfonyl, alkane sulfonyloxy, arylsulfonyloxy, dialkoxy phosphorus acyloxy and two fragrant oxygen phosphorus acyloxy; R ^2dThe alkoxyl group of representative, alkylthio, arylthio, alkyl sulfinyl, fragrant sulfinyl, the alkane alkylsulfonyl, arylsulfonyl, the alkane sulfonyloxy, arylsulfonyloxy, dialkoxy phosphorus acyloxy and two fragrant oxygen phosphorus acyloxy have comprised top R ²Described in those groups.R ^2b, R ^2cAnd R ^2dEach group all can be by at least one at R ²In the substituting group mentioned replace.

At R ²And R ^2aIn; amino can protected 3-amino-1-pyrrolidyl or imino-can protected 1-piperazinyl; its protecting group amino and imino-comprises those protecting groups of using always in this area, for example at Japanese Patent Application Publication (Laid-Open) NO.80, and the amino of mentioning in 665/84 and the GPF (General Protection False group of imino-; as formyl radical; ethanoyl, ethoxycarbonyl, carbobenzoxy-(Cbz); N, N-dimethylaminomethylene etc.

The alkane sulfonyloxy of any replacement of Z representative, arylsulfonyloxy, dialkoxy phosphorus acyloxy and two fragrant oxygen phosphorus acyloxy comprise that those are at R ²In mentioned group, the acyloxy of any replacement of Z representative comprises, for example acetoxyl group and benzoyloxy etc.

The N of formula III, the acetal of N-two substituted formamides comprises the N that knows, the acetal of N-two substituted formamides, N for example, N-two-C _1-5Alkyl formamides two-the C that contracts _1-5Alcohol, as N, the dinethylformamide dimethyl acetal, N, dinethylformamide diethyl acetal, N, dinethylformamide two propyl alcohol that contract, N, dinethylformamide two butanols that contract, N, dinethylformamide two neopentyl alcohols that contract, N, N-diethylformamide dimethyl acetal, N, N-dipropyl methane amide dimethyl acetal, N, N-dibutyl formamide dimethyl acetal etc.N, N-two-C _1-5Alkyl formamides two-the C that contracts _3-6Cycloalkanol is N for example, the dinethylformamide two-hexalin etc. that contracts; N, N-two-C _1-5Alkyl formamides condensed ethandiol or propylene glycol be 2-dimethylamino-1 for example, 3-dioxolane, 2-methylamino-tetramethyl-1,3-dioxolane, 2-dimethylamino-1,3-dioxane etc.; Nitrogenous N-formyl radical saturated heterocyclic shape two-C _1-5Alkyl acetal also can contain Sauerstoffatom in the ring except that nitrogen-atoms, as N-dimethoxy crassitude, and N-dimethoxy methylmorpholine, N-dimethoxy methyl piperidine etc.

By N, the Wei Er David Smail reagent that N-two substituted formamides generate comprises those Wei Er David Smail reagent of knowing by the preparation of N-N-two substituted formamides, especially comprise, for example by the N of formula (VIII), inorganic halides of knowing in N-two substituted formamides and the reaction of Wei Er David Smail or Organohalogen compounds reaction, the Wei Er David Smail reagent that obtains:

R wherein ⁷And R ⁸Can be identical or different groups, represent alkyl or aryl, or form nitrogenous saturated heterocyclic with contiguous nitrogen-atoms, but said ring also sulfur atom-containing or Sauerstoffatom except that nitrogen atom.

The N of formula (VIII), N-two substituted formamides comprise, N for example, N-two-C _1-5The alkyl formamides class, as N, dinethylformamide, N, N-diethylformamide, N, N-dibutyl formamide etc.; N-C _1-5Alkyl-N-aryl carboxamides class is as N-methyl N-formylaniline etc.; N-N-diaryl benzamide type such as N, N-diphenylformamide etc.; The saturated heterocyclyl that contains the N-formyl radical also can contain oxygen or sulphur atom in the ring except that nitrogen-atoms, as the N-carbonyl pyrrolidine, and N-formyl piperidine, N-formyl morpholine and N-formyl radical thiomorpholine etc.

In preparation Wei Er David Smail the reagent inorganic or Organohalogen compounds commonly used, inorganic halides comprises, Phosphorates phosphorus Halides for example, and as phosphoryl chloride, phosphorus oxybromide, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride etc.; Halogenation sulphur class such as thionyl chloride, protobromide sulfonyl, sulfuryl chloride etc.; Or the like.Organohalogen compounds comprise, carbonyl carboxylic acid halides class for example, and as phosgene, trichloromethylchloroformate, chlorocarbonic acid ethyl ester etc.; Oxalyl halogen class, as oxalyl chloride etc., halogenation organic phosphine class is as dibromo triphenyl phosphorane etc.; Or the like.

The salt of above-mentioned each compound comprises, the salt of basic group such as amido etc., the salt of acidic-group such as carboxyl and hydroxyl etc.The salt of basic group comprises, for example with the mineral acid salify, and example hydrochloric acid, bromine hydracid and sulfuric acid etc.; With the organic acid salify, as oxalic acid, citric acid and trifluoroacetic acid etc.; With the sulfonic acid salify, as methylsulfonic acid, tosic acid and naphthene sulfonic acid etc.Comprise during with the acidic-group salify, for example with the basic metal salify, as sodium and potassium etc., with the alkaline-earth metal salify, as magnesium and calcium etc.; Ammonium salt; With nitrogenous organic bases salify, as PROCAINE HCL, PHARMA GRADE, dibenzylamine, N-benzyl-β-phenylethylamine, l-ephenamine, N, N-dibenzyl-ethylenediamin, triethylamine, pyridine, N, accelerine, N-methyl piperidine, N-methylmorpholine, diethylamine and dicyclohexylamine etc.

The method of method of the present invention and preparation compound of the present invention is described in detail in detail below.

(1) formula (V _a) the preparation of compound or its salt, be by by English Patent No.1,409, the formula VI compound or its salt of the methods preparation of 987 narrations with at the will pp1 of association that Frenchifies, 165-1 is 169(1975) with at Englishize association will (C) pp2206-2207(1967) and the 105th Japanese medicine association meeting outline and summary p523(1985) narration formula (VII) the compound or its salt reaction and get.

The used solvent of this reaction can be that this reaction is any solvent of inert, comprises for example water; Alcohols such as methyl alcohol, ethanol, Virahol, butanols, ethylene glycol and methylcyclohexane etc.; Arene such as benzene and toluene etc., halo alkanes such as methylene dichloride, chloroform and ethylene dichloride etc.; Ethers such as tetrahydrofuran (THF) dioxane, phenylmethylether, glycol dimethyl ether and ethylene glycol dimethyl ether etc.; Nitrile such as the second grade; Ketone such as acetone and methylethylketone etc.; Ester class such as methyl acetate and ethyl acetate etc.; Amides such as N, dinethylformamide and N,N-dimethylacetamide etc.; Sulfoxide class such as dimethyl sulfoxide (DMSO) etc.; Or the like.These solvents can use in two or more mixing.

Condensing agent comprises, sodium hydroxide for example, potassium hydroxide, potassium tert.-butoxide, sodium hydride, sodium methylate, sodium ethylate, potassium methylate and potassium ethylate etc.

In this reaction, the consumption of formula (VII) compound or its salt is not critical, yet will wait mole at least with the compound of formula VI, and preferably 1.0-3.0 is than 1.In addition, this reaction is carried out at 0-150 ℃ usually, and preferably 15-100 ℃, the reaction times is 5 minutes to 30 hours.

(2) alkylation

The compound or its salt of formula (V c), the preparation of the compound or its salt of the compound or its salt of formula (II c) and formula (I c), be have or do not have acid binding agent in the presence of, respectively by formula (V compound or its salt a), formula (II compound or its salt and formula (I compound or its salt and alkylating agent reaction a) a).

The solvent that is used for this reaction is that this reaction is any solvent of inert, comprises for example water; Alcohols such as methyl alcohol, ethanol and Virahol etc.; Ethers such as ether, tetrahydrofuran (THF) and dioxane etc., ketone such as acetone and methylethylketone etc.; Ester class such as methyl acetate and ethyl acetate etc.; Arene such as benzene and toluene etc.; Halogenated hydrocarbon such as methylene dichloride and chloroform etc.; Amides such as N, dinethylformamide and N,N-dimethylacetamide etc.; Sulfoxide class such as dimethyl sulfoxide (DMSO) etc.These solvents can two or more mix use.Alkylating agent comprises for example diazonium alkanes, as diazomethane and diazoethane etc.; Sulfuric acid dialkyl class such as methyl-sulfate and ethyl sulfate etc.; Halo alkanes such as methyl iodide, monobromethane and monobromethane etc.; Or the like.

When sulfuric acid dialkyl or haloalkane during, can use acid binding agent as alkylating agent.Acid binding agent comprises for example mineral alkali, as oxyhydroxide and carbonate etc.; Amine such as Trimethylamine 99, triethylamine, Tributylamine, N-methyl piperidine, N-methylmorpholine, lutidine, but power fixed (Colidine) and pyridine etc.As the sulfuric acid dialkyl of alkylating agent or the consumption of haloalkane, and the consumption of the acid binding agent of selecting for use arbitrarily and formula (V compound or its salt a), with formula (II compound or its salt or the formula (molecular ratio of I compound or its salt a) a), mol ratio such as be at least, preferably 1.0-2.0 is than 1.In this case, reaction is carried out at 0-150 ℃ usually, and preferably 0-50 ℃, the reaction times is 5 minutes to 30 hours.

When alkylating agent was used diazoalkane, ((II compound or its salt a), perhaps (amount ratio of I compound or its salt a) was to wait mole to formula to V compound or its salt, formula a) at least, and preferably 1.0-1.5 is than 1 for its consumption and formula.In this case, reaction is carried out at 0-50 ℃ usually, and preferably 0-25 ℃, the reaction times is 5 minutes to 30 hours.

(3) halogenation

(ⅰ) preparation of the compound or its salt class of formula (I b) and (V b) is respectively by formula (I c) and (V compound or its salt and halogenating agent reaction a).The solvent that is used for this reaction is that this reaction is any solvent of inert, comprises for example arene, as benzene, and toluene and dimethylbenzene etc.; Halogenated hydrocarbon such as methylene dichloride, chloroform and ethylene dichloride etc.; Amides such as N, dinethylformamide and N,N-dimethylacetamide etc.; Or the like.These solvents can mix use by two or more.The halo agent comprises for example phosphorus oxychloride, tribromo oxygen phosphorus, phosphorus pentachloride, phosphorus pentabromide, phosphorus trichloride, thionyl chloride photoreactive gas etc.That works that two or more mix to use as solvent for these reagent.(ratio of V compound or its salt a) is to wait mole at least for the consumption of halogenating agent and formula.Reaction is carried out at 0-150 ℃ usually, and preferably 50-110 ℃, the reaction times is 30 minutes to 30 hours.

(ⅱ) formula (preparation of the compound or its salt of I b, be by formula (II compound or its salt a), perhaps formula (II c), (II d), (II h), the compound of (II i) (being the compound or its salt class of formula (II-1)) with by N, the Wei Er David Smail reagent react of N-two substituted formamides gained.The solvent that is used for this reaction is that this reaction is any solvent of inert, comprises for example arene, as benzene, and toluene and dichlorobenzene etc.; Halogenated hydrocarbons such as methylene dichloride, chloroform and ethylene dichloride etc.; Benzamide type such as N, dinethylformamide etc.; Or the like.These solvents can two or more mix use.

When Wei Er David Smail reagent was solution, it can be used as solvent.In this reaction, the consumption of Wei Er David Smail reagent is to wait mole to the ratio of the compound of formula (II-1) at least, and preferably 2.0-5.0 is than 1.Reaction is carried out at 0-150 ℃ usually, and preferably 0-90 ℃, the reaction times is 5 minutes to 30 hours.

By N, N-two substituted formamides gained Wei Er David Smail reagent can be by N, and N-two substituted formamides and above-mentioned inorganic or Organohalogen compounds react with equimolar amount, prepare this Wei Er David Smail reagent and carry out at 0-25 ℃ usually, and the time is 5 minutes to 1 hour.In addition, Wei Er David Smail reagent also can current prepare.

Reaction conditions is not limited to mentioned above, along with the difference of used reaction reagent can be changed condition.

(4) sulfonylation

The compound or its salt of formula (V d), the preparation of the compound or its salt of the compound of formula (II d) and formula (I d), be respectively by formula (V compound or its salt a), formula (II compound or its salt or formula (I compound or its salt a) a), have or do not have acid binding agent in the presence of, react with sulfonated reagent.The solvent that is used for this reaction is that this reaction is any solvent of inert, comprises for example water; Arene such as benzene, toluene and dimethylbenzene etc.; Ethers such as dioxane, tetrahydrofuran (THF), phenylmethylether and diglyme etc.; Halogenated hydrocarbon such as methylene dichloride, chloroform and ethylene dichloride etc.; Ketone such as acetone and methylethylketone etc.; Nitrile such as acetonitrile etc.; Amides such as N, dinethylformamide and N,N-dimethylacetamide etc.; Sulfoxide class such as dimethyl sulfoxide (DMSO) etc.; Hexamethylphosphoramide and pyridine or the like.These solvents can two or more mix use.Sulfonated reagent comprises for example alkane sulfonic acid halide and aryl sulfonyl halides, as methylsulfonyl chloride, and trifluoromethanesulfchloride chloride, ethyl sulfonyl chloride, 1-methyl ethyl sulfonyl chloride, 1,1-dimethyl ethyl sulfonyl chloride, benzene sulfonyl chloride, toluene sulfonyl chloride, nitrobenzene sulfonyl chloride, chlorobenzene sulfonyl chloride, 2.5-two chloro phenylsulfonyl chloride, 2,3,4-trichlorobenzene SULPHURYL CHLORIDE, 2,4,5-trichlorobenzene SULPHURYL CHLORIDE, 2,4, the 6-trimethylbenzene chloride, 2,4,6-triisopropylphenylsulfonyl chloride and naphthalic sulfonic chloride etc.Alkyl sulfonic acid acid anhydride and aromatic sulfonic acid acid anhydride class such as methylsulfonic acid acid anhydride and toluenesulphonic acids acid anhydride etc.; Or the like.In addition, acid binding agent comprises for example mineral alkali and organic bases, as triethylamine, and diisopropylethylamine, 1,8-diazabicyclo (5,4,0) 11 carbon-7-alkene (DBU), pyridine, potassium tert.-butoxide, sodium hydride, oxyhydroxide and carbonate etc.

(V compound or its salt a), (II compound or its salt a), perhaps (amount ratio of I compound or its salt a) such as is at least at mole to formula to formula, and preferably 1.0-2.0 is than 1 for the consumption of the consumption of sulfonated reagent and the acid binding agent of selecting for use arbitrarily and formula.Reaction is carried out at-10-150 ℃ usually, and preferably 0-80 ℃, the time is 5 minutes to 30 hours.

(5) mercaptanization

For compound by the compound formula (II e) of the compound or its salt of formula (II b) or formula (II d), compound or its salt by the compound or its salt preparation formula (V e) of formula (V b) or (V d), have or do not have acid binding agent in the presence of, formula (II b), (II d), the compound or its salt of (V b) or (V d) can with mercaptan or its reactant salt, as thiomethyl alcohol, sulfur alcohol, propane thiol, 1-methyl sulfur alcohol, isobutyl mercaptan, 1,1-dimethyl sulfur alcohol, pentan-thiol, hexylmercaptan, heptanthiol, spicy thioalcohol, dodecyl mercaptans, thiophenol and thionaphthol etc.The salt of mercaptan comprises, for example as salt of the acidic-group of being narrated under the compound situation of formula I etc.Reacting used solvent is that this reaction is any solvent of inert, comprises for example arene, as benzene, and toluene and dimethylbenzene etc.; Ethers such as dioxane, tetrahydrofuran (THF), phenylmethylether and diethyl carbitol etc.; Halogenated hydrocarbon such as methylene dichloride, chloroform and ethylene dichloride etc.; Amides such as N, dinethylformamide and N,N-dimethylacetamide etc.; Sulfoxide class such as dimethyl sulfoxide (DMSO) etc.; Or the like.These solvents can two or more mix use.Acid binding agent comprises, for example inorganic base such as oxyhydroxide, sodium hydride and carbonate etc.; Organic bases such as Trimethylamine 99, triethylamine, diisopropyl ethyl amine, DBU, potassium tert.-butoxide, Tributylamine, pyridine, the N-methyl piperidine, N-methylmorpholine, lutidine and Ke Li are fixed etc.The consumption of the consumption of mercaptan or its salt and the acid binding agent of selecting for use arbitrarily, with the compound of formula (II b) or (II d) or with the ratio of the compound or its salt class of formula (V b) or (V d), be to wait mole at least, preferably 1.0-2.0 is than 1.Reaction is carried out at 0-150 ℃ usually, and preferably 0-70 ℃, the time is 5 minutes to 30 hours.

(6) phosphorylated

Formula (I i), the preparation of the compound or its salt of (II i) and (V i), be have or do not have acid binding agent in the presence of (I a), (II a) and (V compound or its salt a) reacts with phosphorylating agent by formula respectively.

The solvent that is used for this reaction is that this reaction is any solvent of inert, those used solvent phosphorus esterification reagents of particularly above-mentioned sulfonylation comprise, dialkyl group phosphoryl halogen for example is as solutions of dimethyl phosphoryl chlorine, diethylchlorophosphate (C2H5O)2P(O)Cl, dipropyl phosphoryl chloride and dibutyl phosphoryl chloride etc.; Diaryl phosphoryl halogen such as diphenyl phosphoryl chloride etc.; Or the like.

The used acid binding agent of the acid binding agent that is used for this reaction and above-mentioned sulfonylation is identical.(I a), (II a) or (the V a) ratio of compound or its salt such as is at least at a mole, is preferably 1.0-1.5 than 1 for the consumption of phosphorus esterification reagent and the acid binding agent consumption of selecting for use arbitrarily and formula.Reaction is carried out at 0-150 ℃ usually, and preferably 0-50 ℃, the reaction times is 5 minutes to 30 hours.

(7) azide

The preparation of the compound or its salt of the compound of formula (II j) or formula (I j) and (V j), be have or do not have acid binding agent in the presence of, respectively by formula (II compound or its salt a), and formula (I a) and (V compound or its salt and azide reagent react a).Used solvent can be that this reaction is any solvent of inert, especially used those solvents in above-mentioned sulfonylation.

Azide reagent comprises, dialkyl group phosphoryl azide thing for example is as diethyl phosphoryl azide thing etc.; Diaryl phosphoryl azide thing such as diphenylphosphine acylazide thing etc.; Or the like.Used acid binding agent especially comprises the identical acid binding agent that above-mentioned sulfonylation is used.

The consumption of azide reagent and the acid binding agent selected for use arbitrarily, (I a), (II a) or (amount ratio of V compound or its salt a) is equimolar at least, and preferably 1.0-3.0 is than 1 with formula.Reaction is normally carried out at 0-150 ℃, and preferably 15-100 ℃, the reaction times is 5 minutes to 30 hours.

(8) oxidation

The preparation of formula (II g) and (II h) compound, be the compound of formula (II e) under corresponding condition with the oxidant reaction gained; The preparation of formula (I g) and (I h) compound or its salt class be the compound or its salt of formula (I e) under corresponding condition with the oxidant reaction gained; The preparation of the compound or its salt class of formula (V g) and (V h), be the compound of formula (V e) under corresponding condition with the oxidant reaction gained.

The used solvent of top oxidizing reaction can be that this reaction is any solvent of inert, arene is for example arranged, as benzene toluene and dimethylbenzene etc.; Halogenated hydrocarbon such as methylene dichloride, chloroform and ethylene dichloride etc.; Ethers such as ether, tetrahydrofuran (THF) and dioxane etc.; Fatty acid such as formic acid and acetate etc., and water or the like.These solvents can two or more mix use.Oxygenant comprises, for example organic peracid such as peroxyformic acid, peracetic acid, peroxybenzoic acid and metachloroperbenzoic acid etc.; Hydrogen peroxide; Periodic acid; Sodium metaperiodate; Potassium metaperiodate, potassium permanganate and ozone or the like.

Be the compound of preparation formula (II g), the perhaps compound or its salt class of formula (I g) and (V g) (sulfoxide class), oxygenant is preferably used the organic peracid class, sodium metaperiodate and potassium metaperiodate etc.The consumption of oxygenant is a 1.0-1.2 mol ratio 1 to the amount ratio of the compound or its salt of the compound of formula (II e) or formula (I e) or (V e),

Be the compound of preparation formula (II h), the perhaps compound or its salt (sulfone) of formula (I h) and (V h), oxygenant is preferably used organic peracid class and hydrogen peroxide etc.; The amount ratio of the compound or its salt class of the compound of the consumption of oxygenant and formula (II e) or formula (I e) or (V e) is 2.0-2.5 mol ratio 1.The compound or its salt of the compound of formula (II g) or formula (I g) or (V g) can further be oxidized to sulfone in case of necessity.These reactions are carried out at 0-100 ℃ usually, and preferably 0-30 ℃, 5 minutes to 30 hours reaction times.

(9) preparation of the compound or its salt of formula (V f), can have or do not have acid binding agent in the presence of, the compound or its salt of formula (V b) or (V d) and the amine of formula IV or its reactant salt, the preparation of the compound or its salt of formula (II f), can have or do not have acid binding agent in the presence of, by the amine reaction of the compound of formula (II b) or (II d) and formula IV and get.

The solvent that reacts used can be that this reaction is any solvent of inert, comprises for example arene, as benzene, and toluene and dimethylbenzene etc.; Alcohols such as methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, the isopropylcarbinol and the trimethyl carbinol etc.; Ethers such as dioxane, tetrahydrofuran (THF), phenylmethylether and diethyl carbitol etc.; Ketone such as acetone and methylethylketone etc.; Nitro alkanes such as Nitromethane 99Min. and nitroethane etc.; Ester class such as methyl acetate and ethyl acetate etc.; Nitrile such as acetonitrile etc.; Halogenated hydrocarbon such as methylene dichloride, chloroform and ethylene dichloride etc.; Amides such as N, dinethylformamide and N,N-dimethylacetamide etc.; Sulfoxide class such as dimethyl sulfoxide (DMSO) etc.; Or the like.These solvents can two or more mix use.In addition, acid binding agent comprises above-mentioned those acid binding agents that are used for sulfonylation.

The amine of formula IV or the consumption of its salt, when without acid binding agent, with the compound or its salt of formula (V b), the compound or its salt of formula (V d), the amount ratio of the change of the compound of formula (II b) or formula (II d), preferably the 2.0-5.0 mol ratio 1; If use acid binding agent, then can suitably reduce the consumption of amine.

Above-mentioned reaction is carried out at 0-150 ℃ usually, and preferably 0-100 ℃, the reaction times is 5 minutes to 30 hours.

(10) formula (II a), (II b), (II c), (II d), (II e), (II f), (II g), (II h), the compound or its salt of (II i) and (II j) (is the preparation of the compound or its salt class of formula II, can be by formula (V a), (V b), (V c), (V d), (V e), (V f), (V g), (V h), (V i) and V j) compound or its salt (being the compound or its salt class of formula (V-1)) carry out as follows:

In the following formula, R ^1a, R ²With the implication of X as mentioned above, R ^1bRepresentative is included in as R ^1aThe carboxy protective agent of identical instances, and can with R ^1aIdentical or different.

The active derivative of carboxylic acid comprises in the compound of formula (V-1), and carboxylic acid halides for example is as acyl chlorides and acylbromide etc.; Acid anhydrides and the mixed acid anhydride that generates with the carbonic acid mono ethyl ester; Active ester class such as dinitrobenzene phenyl ester, cyanomethyl ester and succinimide ester etc.; The active amide that forms with imidazoles etc.; Or the like.

The salt of the compound of formula (IX-1) and (IX-2) comprises, for example the salt that forms with basic metal such as lithium, potassium and sodium etc.; Salt with formation such as alkaline-earth metal such as magnesium; The salt that forms with magnesium ethylate etc.; Or the like.

In addition, the salt of the compound of formula (X) comprises as the mentioned same salt of salt at the compound of formula I; Or the like.

The preparation of the compound or its salt of formula II or (X) can be by the active derivative of carboxyl of the compound of formula (V-1), in appropriate solvent respectively with the compound or its salt of formula (IX-2) or with the compound or its salt reaction of formula (IX-1).Used solvent can be that this reaction is any solvent of inert, for example alcohols such as methyl alcohol, ethanol and Virahol etc.; Arene such as benzene and toluene etc.; Halogenated hydrocarbon such as methylene dichloride, chloroform and ethylene dichloride etc.; Ethers such as ether, tetrahydrofuran (THF) and dioxane etc.; Nitrile such as acetonitrile etc.; Amides such as N, dinethylformamide and N,N-dimethylacetamide etc.; Or the like.In addition, the consumption of the compound or its salt of formula (IX-1) or (IX-2) with the amount ratio of the active derivative of carboxyl of the compound of formula (V-1), is equimolar at least, and preferably the 1.0-2.5 mol ratio 1.Reaction is carried out at-50-100 ℃ usually, be preferably in-20-70 ℃ carries out, and the reaction times is 5 minutes to 30 hours.

For the compound or its salt with formula (X) becomes the compound or its salt of formula II, can be with the R of the compound or its salt of formula (X) ¹Carboxyl-protecting group is removed, and with trifluoroacetic acid in phenylmethylether or tosic acid decarboxylic reaction takes place in aqueous solvent.

(11) ring-closure reaction

For by formula (II a), (II b), (II c), (II d), (II e), (II f), (II g), (II h), the compound or its salt class of (II i) and (II j) (being the compound or its salt class of formula II), preparation formula (I a), (I b), (I c), (I d), (I e), (I f), (I g), (I h), the compound or its salt class of (I i) and (I j) (being the compound or its salt class of formula (I-4)), can have or solvent-free in the presence of, respectively by the compound or its salt of formula II and the N of formula III, the aldolization of N-two substituted formamides.

The solvent that reacts used can be that this reaction is any solvent of inert, comprises for example arene, as benzene, and toluene and dimethylbenzene etc.; Halogenated hydrocarbon such as methylene dichloride, chloroform and ethylene dichloride etc.; Ethers such as dioxane, tetrahydrofuran (THF) and diglyme etc.; Ester class such as methyl acetate and ethyl acetate etc.; Ketone such as acetone and methylethylketone etc.; Nitrile such as acetonitrile etc.; Alcohols such as methyl alcohol and ethanol etc.; Amides such as N, dinethylformamide and N,N-dimethylacetamide etc.; Sulfoxide class such as dimethyl sulfoxide (DMSO) etc.; Pyridine or the like.These solvents can two or more mix use.

The N of formula III, the acetal consumption of N-two substituted formamides, the amount ratio with the compound or its salt of formula II is equimolar at least, and can be used as the excessive use of solvent.In addition, add acid anhydrides such as acetic anhydride, this reaction is carried out smoothly.In this case, the amount ratio of the acid anhydrides amount of adding and the compound or its salt of formula II is equimolar at least, and preferably the 1.0-5.0 mol ratio 1.Reaction is to finish in 30 hours at 5 minutes under 0-150 ℃ in temperature usually.In addition, the N of formula III, the acetal of N-two substituted formamides can prepare in this reactive system.The intermediate of the compound or its salt of production in reaction (XI):

R in the formula ^1a, R ², R ⁵, R ⁶With the implication of X as mentioned above.Above-mentioned intermediate can be isolated according to a conventional method; Yet if do not separate above-mentioned intermediate, it can be transformed into the compound or its salt of formula I.When the midbody compound of separate type (XI) or its salt, have or anacidity in the presence of, closed loop can take place, obtain the compound or its salt of formula I.The solvent that is used for ring-closure reaction can be that this reaction is any solvent of inert, as the used same solvent of above-mentioned reaction, fatty acid such as formic acid and acetate etc.; Water or the like.These solvents can two or more mix use, and the acid of selecting for use arbitrarily comprises, mineral acid example hydrochloric acid for example, bromine hydracid and sulfuric acid etc.; Organic carboxyl acid class such as oxalic acid and trifluoracetic acid etc.; Sulfonic acid class such as methylsulfonic acid, tosic acid and naphthene sulfonic acid etc.; Or the like.These sour consumptions compound amount common and formula (XI) is equimolar at least.Reaction is carried out at 0-150 ℃ usually, and the time is 5 minutes to 30 hours.

Moreover, the preparation of the compound or its salt of formula I, also can have or do not have diacetyl oxide in the presence of, by orthoformate alkyl ester and N, the aldolization of the dibasic methane amide of N-.Be reflected at or solvent-free existence under carry out, solvent can be that this reaction is any solvent of inert, arene is for example arranged, as benzene, toluene and dimethylbenzene etc.; Ethers such as dioxane, tetrahydrofuran (THF), glycol dimethyl ether and ethylene glycol dimethyl ether etc.; Halogenated hydrocarbon such as methylene dichloride, chloroform and ethylene dichloride etc.; Alcohols such as methyl alcohol and ethanol etc.; Ester class such as methyl acetate and ethyl acetate etc.; Amides such as N, dinethylformamide and N,N-dimethylacetamide etc.; Sulfoxide class such as dimethyl sulfoxide (DMSO) etc.; Or the like.These solvents can two or more mix use.In addition, orthoformate alkyl ester comprises that trimethyl orthoformate and triethyl orthoformate etc. can be used as solvent and use.The amount ratio of the consumption of ortho-formiate and the compound or its salt of formula II such as preferably is at least at a mole.Reaction is carried out at 0-150 ℃ usually, and preferably 15-110 ℃, the time is 5 minutes to 30 hours.

(12) with the substitution reaction of amine

For by formula (I d), (I e), (I g), (I h), (I i), the compound or its salt class of the compound or its salt class of (I j) (being the compound or its salt class of formula (I-2)) preparation formula (I-1), have or do not have acid binding agent in the presence of, the compound or its salt class of formula (I-2) and amine or its reactant salt of formula IV.The solvent that reacts used can be that this reaction is any solvent of inert, for example, and alcohols such as methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, the isopropylcarbinol and the trimethyl carbinol etc.; Ethers such as dioxane, tetrahydrofuran (THF), phenylmethylether and diethyl carbitol etc.; Ketone such as acetone and methylethylketone etc.; Nitro alkanes such as Nitromethane 99Min. and nitroethane etc.; Ester class such as methyl acetate and ethyl acetate etc.; Nitrile such as acetonitrile etc.; Arene such as benzene, toluene and dimethylbenzene etc.; Halogenated hydrocarbon such as methylene dichloride; Chloroform and ethylene dichloride etc.; Amides such as N, dinethylformamide and N,N-dimethylacetamide etc.; Sulfoxide class such as dimethyl sulfoxide (DMSO) etc.; Or the like.These solvents can two or more mix use.

Acid binding agent comprises, for example organic bases or inorganic base, and as triethylamine, diisopropylethylamine, DBU, pyridine, potassium tert.-butoxide, salt of wormwood, yellow soda ash and sodium hydride etc.

The amine of formula IV or the consumption of its salt, without acid binding agent the time, the amount ratio of the compound or its salt class of it and formula (I-2) is 2.0-5.0 mol ratio 1 preferably, when using acid binding agent, can suitably reduce its consumption.

This reaction is carried out at 0-150 ℃ usually, and preferably 0-100 ℃, the time is 5 minutes to 30 hours.

In the compound or its salt of the formula (I d) of above-mentioned reaction, radicals R ¹⁰SO ₃-preferably bulky alkane sulfonyloxy or arylsulfonyloxy, preferably in arylsulfonyloxy, the adjacent carbons of the carbon atom that links to each other with the oxygen alkylsulfonyl is replaced by above-mentioned substituting group.

The compound that above-mentioned each step reaction obtains can randomly be removed protecting group with known method, to obtain corresponding free carboxy acid.And then this free carboxy acid salt-forming reaction or the esterification chosen wantonly with known method, generate corresponding salt or ester.

The compound that above-mentioned reaction obtains can separate with conventional method, maybe needn't separate and is directly used in the reaction of back.

Method of the present invention is for the compound or its salt of preparation formula (I-1) and without 2,6-two chloro-5-fluoropyridine derivatives, industrial be very easily.2, the 24th the international chemotherapy that 6-two chloro-5-fluoropyridine derivatives are spoken of in the above and outline and the summary and Japanese Patent Application Publication (Laid-Open) No.228 of antimicrobial agents meeting are a kind of intermediate in 479/85 the method.(this derivative medically can cause damage, as erythema etc.).

Be anti-microbial activity below with the typical compound of method preparation of the present invention.

Test method

Standard method (chemotherapy according to Japanese chemotherapy association, 29(1), 76-79(1981)), the bacterial solution (Eiken Kagaku manufacturing) that obtains in the heart infusion culture medium culturing is incubated 20 hours for 37 ℃, be seeded on the heart infusion agar that contains medicine, and, measure the minimum concentration MIC(μ g/ml of bacteria growing inhibiting afterwards) in 37 ℃ of cultivations 20 hours.The amount of bacteria that temperature is incubated is 10 ⁴Cell/plate (10 ⁸Cells/ml) table 1 has been listed the MIC value of following test-compound:

Table 1

X F H

Bacterium

Golden suis FDA209P ≦ 0.05 ≦ 0.05

Epidermis IID886 ≦ 0.05 0.1

Golden suis F-137 ^*≦ 0.05 0.1

Intestinal bacteria NIHJ ≦ 0.05 ≦ 0.05

Intestinal bacteria TK-111 ≦ 0.05 ≦ 0.05

Intestinal bacteria GN5482 ^*≦ 0.05 ≦ 0.05

Copper wire look utmost point hair bacillus S-68 0.02 0.2

Acinetobacter anitratus A-6 ≦ 0.05 ≦ 0.05

Copper wire look utmost point hair bacillus IFO3445 0.2 0.2

Copper wire look utmost point hair bacillus GN918 ^*0.1 0.1

*: penicillinase-generation bacterium * *: cephalosporinase-generation bacterium

The compound or its salt of formula (I-1) is when medicinal, and the vehicle of using with the conventional medicine preparation suitably share, and makes tablet, capsule, pulvis, syrup, granule, suppository, salve and injection etc. with conventional method.Symptom according to patient can have different route of administration, dosage and administration number of times.Normally oral or non-through stomach and intestine administration (for example, injection is instiled and rectal administration), press 0.1-100mg/kg/ days dosage once or divide the several administration.

The following describes example of the present invention, these examples are not to be limitation of the present invention, and just are illustrated.

Symbol implication in the example is as follows:

Me: methyl, Et: ethyl, n-pr: n-propyl,

I-pr: sec.-propyl, Ac: ethanoyl

Example 1

(1) suspension 50g β-imino--β-phenoxy propionic acid carbethoxy hydrochloride and 27.8g 2,4 difluorobenzene amine in the 300ml ethyl acetate, gained suspension returning reaction 2 hours.The crystallization that filtering-depositing goes out also washes twice with ethyl acetate, and each 200ml obtains 47g(productive rate 82.2%) the N-(2.4-difluorophenyl) the amidino groups ethyl acetate hydrochloride, m.p.:196-197 ℃.

IR（KBr）Cm ^-1：νc＝01730

NMR(DMSO-d ₆) the δ value:

1.26（3H，t，J＝7Hz），4.07（2H，S），

4.19（2H，q，J＝7Hz），7.02-7.78（3H，m），

9.11（1H，b _s），10.26（1H，b _s），12.28（1H，b _s）

With above-mentioned same method, make following compound:

ON-(2, the 4-difluorophenyl) amidino groups methyl acetate hydrochloride

m.P：192-193℃

IR（KBr）Cm ^-1：νc＝0 ¹⁷³⁵

NMR(DMSO-d ₆) the δ value:

3.74（3H，S），4.09（2H，S），6.91-7.73（3H，m），

9.15（1H，bS），10.31（1H，bS），12.29（1H，bS）

The ON-(4-fluorophenyl) amidino groups methyl acetate hydrochloride

m.P.：134-135℃

IR（KBr）Cm ^-1：νc＝0 ¹⁷³⁰

NMR σ (DMSO-d ₆) the δ value:

3.74（3H，S），4.05（2H，S），7.01-7.59（4H，m），

8.96（1H，bS），10.06（1H，bS），12.26（1H，bS）

(2) with 23.0gN-(2, the 4-difluorophenyl) amidino groups methyl acetate hydrochloride is dissolved in the mixture of 92ml water and 92ml methylene dichloride, regulate this solution to PH13 with the 2N aqueous sodium hydroxide solution, tell organic layer, successively with 50ml water and the washing of 50ml saturated sodium-chloride water solution, anhydrous magnesium sulfate drying.Dried solution adds 27.1g α-formyl radical-α-ethyl fluoroacetate sodium salt under room temperature, gained mixture back flow reaction 4 hours, and then, underpressure distillation desolventizes.In the gained resistates, add 92ml water and 46ml ethyl acetate, filter and collect the crystallization of separating out.The gained crystallization is suspended in the 184ml water and with 6N hydrochloric acid regulates this suspension to PH1.0, in the gained crystallization, add 46ml water and 46ml Virahol, then, filter and collect crystallization, obtain 15.0g(productive rate 57.0%) 2-(2,4-two fluoroanilino)-and 5-fluoro-6-hydroxy niacin methyl esters, m.P.222-223 ℃.

M.P.:222-223 ℃ (re-crystallizing in ethyl acetate)

IR（KBr）Cm ^-1：νc＝0 ¹⁷⁰⁰

NMR(TFA-d ₁) the δ value:

4.06（3H，S），6.71-7.65（3H，m），8.12（1H，d，J＝11Hz）

With above-mentioned same method, obtain following compound:

O2-(2,4-two fluoroanilino)-5-fluoro-6-hydroxy niacin ethyl ester

M.P.:177-178 ℃ (re-crystallizing in ethyl acetate)

IR（KBr）Cm ^-1νc＝0 ¹⁷⁰⁰

NMR(TFA-d ₁) the δ value:

1.52（3H，t，J＝7Hz），4.50（2H，q，J＝7Hz）

6.80-7.65（3H，m），8.15（1H，d，J＝11Hz）

O5-fluoro-2-(4-fluoroanilino)-6-hydroxy niacin methyl esters

M.P.227-228 ℃ (re-crystallizing in ethyl acetate)

IR（KBr）Cm ^-1：νc＝0 ¹⁶⁹⁰

NMR(TFA-d ₁) the δ value:

4.05（3H，S），6.89-7.53（4H，m），

8.11（1H，d，J＝11Hz）

(3) amidino groups methyl acetate hydrochloride dissolving 500mg N-(2 in the mixture of 5ml water and 5ml methylene dichloride, 4-difluorophenyl), and gained solution is adjusted to PH13.0 with the 2N aqueous sodium hydroxide solution.Tell organic layer and use the washing of 3ml water and 3ml saturated sodium-chloride water solution successively, then, with anhydrous magnesium sulfate drying.In gained solution, add 820mg 3-(4-Methyl benzenesulfonyl oxygen base)-2-fluoropropenes acetoacetic ester, and under room temperature, add 120mg sodium methylate (purity:, then, under same temperature, allow gained mixture reaction 24 hours 92-3%) with 5ml methyl alcohol.Underpressure distillation desolventizes, and adds 10ml water and 2ml ethyl acetate in the gained resistates.Regulate gained solution to pH1.0 with 6N hydrochloric acid, filter the crystallization that collecting precipitation goes out, and use 2ml water and 2ml washed with isopropyl alcohol successively, obtain 370mg(productive rate 65.7%) 2-(2.4-two fluoroanilino)-5-fluoro-6-hydroxy niacin methyl esters.The physical properties of this compound is identical with top (2) gained compound.

(4) repeat the method for top (3), but replace 3-(4-Methyl benzenesulfonyl oxygen base with the 2-fluoro acrylic ester that a kind of 3-shown in the table 2 replaces)-2-fluoropropenes acetoacetic ester, gained

The physical properties of each reaction gained compound is identical with top (2) gained compound.

Example 2

In the 6ml tetrahydrofuran (THF), dissolve 200mg2-(2,4-two fluoroanilino)-5-fluoro-6-hydroxyl-nicotinic acid methyl ester, the diethyl ether solution of the about 40mg diazomethane of adding under the ice bath cooling, this mixture reacted under room temperature 30 minutes.Then, add acetic acid and no longer bubble until this reaction mixture, then, underpressure distillation desolventizes.With the crystallization of 6ml washed with isopropyl alcohol gained, obtain 150mg(productive rate 71.6%) 2-(2,4-two fluoroanilino)-5-fluoro-6-methoxyl group nicotinic acid methyl ester, m.P.160-161 ℃.

M.P.:160.5-161.5 ℃ (re-crystallizing in ethyl acetate)

IR（KBr）Cm ^-1：νc＝0 ¹⁶⁹⁰

NMR(CDCl ₃) the δ value:

3.89（3H，S），3.98（3H，S），6.57-7.08（2H，m），

7.81（1H，d，J＝11Hz），8.10-8.97（1H，m），

10.24（1H，bs）

Example 3

In 5ml N, dissolve 200mg2-(2 in the dinethylformamide, 4-two fluoroanilino)-5-fluoro-6-hydroxy niacin methyl esters, in gained solution, adding 110mg salt of wormwood and 93mg methyl-sulfate under the room temperature, then, the gained mixture reacted 2 hours under same temperature.Then, in reaction mixture, add 20ml water and 20ml ethyl acetate, tell organic layer, successively with 10ml water and the washing of 10ml saturated sodium-chloride water solution, anhydrous magnesium sulfate drying.Underpressure distillation desolventizes, and adds the 5ml Virahol in the gained crystallisate, then, filters and collects crystallization, obtains 180mg(productive rate 86.0%) 2-(2,4-two fluoroanilino)-5-fluoro-6-methoxyl group nicotinic acid methyl ester.The physical properties of this compound is identical with example 2 gained compounds.

Example 4

At 5ml N, dissolving 200mg 2-(2 in the dinethylformamide, 4-two fluoroanilino)-5-fluoro-6-hydroxy niacin methyl esters, then, under room temperature, add 110mg salt of wormwood and 0.11g methyl iodide, and under same temperature, make gained mixture reaction 1 hour.In reaction mixture, add 20ml water and 20ml ethyl acetate, tell organic layer, successively with 10ml water and the washing of 10ml saturated sodium-chloride water solution, anhydrous magnesium sulfate drying.Underpressure distillation desolventizes and add the 5ml Virahol in the gained crystallisate, then, filters and collects crystallization, obtains 190mg(productive rate 90.7%) 2-(2,4-two fluoroanilino)-5-fluoro-6-methoxyl group nicotinic acid methyl ester.The physical properties of this compound is identical with example 2 gained compounds.

Example 5

9.5g 2-(2,4-two fluoroanilino)-5-fluoro-6-hydroxy niacin methyl esters, 26.5g phosphorus pentachloride and 46.9g phosphoryl chloride were in 70-80 ℃ of reaction 4 hours.Then, slowly add 285ml water in the reaction mixture, filter crystallization that collecting precipitation goes out and with the 57ml water washing.By crystallization (WaKo silica gel C-200, eluent: toluene) obtain 3.5g(productive rate 34.7%) the 6-chloro-2-(2 of column chromatography purification gained, 4-two fluoroanilino)-5-fluorine nicotinic acid methyl esters, mp.137-139 ℃.

M.p.:139.5-140.5 ℃ (diisopropyl ether recrystallization)

IR（KBr）Cm ^-1：νc＝0 ¹⁶⁹⁵

NMR(CDCl ₃) the δ value:

3.93（3H，s），6.61-7.06（2H，m），

7.94（1H，d，J＝9Hz），8.15-8.57（1H，m），

10.13（1H，bs）

Example 6

Suspension 500mg 2-(2 in the 10ml methylene dichloride, 4-two fluoroanilino)-5-fluoro-6-hydroxy niacin methyl esters, in gained suspension, add 440mg 2,4,6-trimethylbenzene chloride and 220mg triethylamine, then, the gained mixture reacted under room temperature 3 hours.In this reaction solution, add 15ml water, tell organic layer, with 15ml water washing, anhydrous magnesium sulfate drying.Underpressure distillation desolventizes and add the 15ml ether in the gained crystallisate, then, filters the collection crystallization and obtains 660mg(productive rate 81.9%) 2-(2,4-two fluoroanilino)-5-fluoro-6-(2,4,6-Three methyl Benzene sulfonyloxy) nicotinic acid methyl ester, mp.153-155 ℃.

M.p.:155-156 ℃ (re-crystallizing in ethyl acetate)

IR（KBr）Cm ^-1：νc＝0 ¹⁷⁰⁰

NMR(CDCl ₃) the δ value:

2.33（3H，s），2.59（6H，s），3.92（3H，s），

6.32-6.84（2H，m），6.92（2H，s），

7.35-7.94（1H，m），8.05（1H，d，J＝9Hz）

10.17（1H，bs）

With top same method, obtain following compound:

02-(2,4-two fluoroanilino)-5-fluoro-6-mesyloxy nicotinic acid methyl ester,

M.p.:120-121 ℃ (re-crystallizing in ethyl acetate)

IR（KBr）Cm ^-1：νc＝0 ¹⁶⁹⁰

NMR(CDCl ₃) the δ value:

3.30（3H，s），3.94（3H，s），6.60-7.15（2H，m），

0 2-(2,4-two fluoroanilino)-5-fluoro-6-(2,4,6-tri isopropyl benzenesulfonyl oxygen base) Nikithan

M.p:147-148 ℃ (re-crystallizing in ethyl acetate)

IR（KBr）Cm ^-1：νc＝0 ¹⁷⁰⁰

NMR(CDCl ₃) the δ value:

1.21（12H，d，J＝7Hz），1.28（6H，d，J＝7Hz），

1.40（3H，t，J＝7Hz），2.55-3.30（1H，m），

Example 7

In 7ml N, suspension 700mg 6-chloro-2-(2 in the dinethylformamide, 4-two fluoroanilino)-5-fluorine nicotinic acid methyl esters, and in gained suspension, adding 340mg triethylamine and 210mg mercaptan under the room temperature, then, the gained mixture reacted 4 hours down in 50 ℃.Then, in reaction mixture, add 40ml ethyl acetate and 30ml water, and with 2N hydrochloric acid conditioned reaction mixture to PH2.Tell organic layer, successively with 20ml water and the washing of 20ml saturated sodium-chloride water solution, anhydrous magnesium sulfate drying.Underpressure distillation desolventizes, and adds the 10ml hexane in the gained crystallisate, then, filters and collects the gained crystallization, obtains 620mg(productive rate 81.9%) 6-ethylmercapto group-2-(2,4-two fluoroanilino)-5-fluorine nicotinic acid methyl esters, m.p.113-114 ℃.

M.p:113.5-114 ℃ (diisopropyl ether recrystallization)

IR（KBr）Cm ^-1：νc＝0 ¹⁶⁸⁰

NMR(CDCl ₃) the δ value:

1.29（3H，t，J＝7Hz），3.07（2H，q，J＝7Hz），

3.90（3H，s），6.50-7.20（2H，m），

7.66（1H，d，J＝10Hz），7.80-8.50（1H，m），

10.00（1H，bs）

With top same method, obtain 2-(2,4-two fluoroanilino)-5-fluoro-6-thiophenyl nicotinic acid methyl ester.

M.p.:128-128.5 ℃ (diisopropyl ether recrystallization)

IR（KBr）Cm ^-1：νc＝0 ¹⁶⁸⁵

NMR(CDCl ₃) the δ value:

10.25（1H，bs）

Example 8

At 10ml N, suspension 1.00g 6-chloro-2-(2 in the dinethylformamide, 4-two fluoroanilino)-5-fluorine nicotinic acid methyl esters, in gained suspension, add 750mg 3-amino-pyrrolidine dihydrochloride and 1.44g triethylamine, then, the gained mixture reacted 30 minutes down in 70 ℃.Then, in reaction mixture, add 50ml chloroform and 50ml water, tell organic layer, successively with 25ml water and the washing of 25ml saturated sodium-chloride water solution, anhydrous magnesium sulfate drying.Underpressure distillation removes and desolvates, and adds the 5ml ether in the gained crystallisate, then, filters and collects crystallization, obtains 1.10g(productive rate 95.1%) 6-(3-amino-1-pyrrolidyl)-2-(2,4-two fluoroanilino)-5-fluorine nicotinic acid methyl esters, m.p.139-140 ℃.

IR（KRV）Cm ^-1：νc＝0 ¹⁶⁷⁰

NMR(CDCl ₃) the δ value:

6.57-7.12（2H，m），7.58（1H，d，J＝14Hz）

8.10-8.62（1H，m），10.32（1H，bs）

With top same method, obtain 6-(4-ethanoyl-1-piperazinyl)-2-(2,4-two fluoroanilino)-5-fluorine nicotinic acid methyl esters.

M.p.:172-173 ℃ (re-crystallizing in ethyl acetate)

IR（KBr）Cm ^-1：νc＝0 ^1680，1650

NMR(CDCl ₃) the δ value:

6.57-7.07（2H，m），7.68（1H，d，J＝13Hz），

7.77-8.18（1H，m），10.05（1H，bs）

Example 9

Dissolving 650mg 6-(3-amino-1-pyrrolidyl in the 6.5ml chloroform)-and 2-(2,4-two fluoroanilino)-5-fluorine nicotinic acid methyl esters, and in gained solution, add the 190mg acetic anhydride, then, the gained mixture reacted under room temperature 10 minutes.Underpressure distillation removes and desolvates.In the gained crystallisate, add the 2ml ether, then, filter and collect crystallization, obtain 720mg(productive rate 99.4%) 6-(3-acetylaminohydroxyphenylarsonic acid 1-pyrrolidyl)-2-(2,4-two fluoroanilino)-5-fluorine nicotinic acid methyl esters,

m.p.199-200℃

M.p.202-203 ℃ (re-crystallizing in ethyl acetate)

IR（KBr）Cm ^-1：νc＝0 ¹⁶⁷⁵

NMR(CDCl ₃-DMSO-d ₆) the δ value:

6.63-7.17（2H，m），7.62（1H，d，J＝14Hz），

7.83-8.60（2H，m），10.30（1H，bs）

Example 10

At 3ml N, suspension 120mg 3-amino-pyrrolidine dihydrochloride in the dinethylformamide, and in gained suspension, add the 250mg triethylamine, then, the gained mixture reacted under room temperature 5 minutes.In reaction mixture, add 300mg2-(2,4-two fluoroanilino)-5-fluoro-6-(2,4,6-Three methyl Benzene sulfonyloxy) nicotinic acid methyl ester, the gained mixture reacted under room temperature 1.5 hours.Add 10ml chloroform and 10ml water in this reaction mixture, tell organic layer, successively with 10ml water and the washing of 10ml saturated sodium-chloride water solution, then, with anhydrous magnesium sulfate drying.Then, add the 100mg acetic anhydride in organic layer, the gained mixture reacted under room temperature 10 minutes, and then, underpressure distillation removes and desolvates.In the gained crystallisate, add the 5ml ether, filter and collect crystallization, obtain 210mg(productive rate 82.4%) 6-(3-acetylaminohydroxyphenylarsonic acid 1-pyrrolidyl)-2-(2,4-two fluoroanilino)-5-fluorine nicotinic acid first vinegar.The physical properties of this compound is identical with example 9 gained compounds

Obtain 6-(4-ethanoyl-1-piperazinyl with top same method)-2-(2,4-two fluoroanilino)-5-fluorine nicotinic acid methyl esters.

The physical properties of this compound is identical with example 8 gained compounds.

Example 11

At 39ml N, dissolving 3.89g 2-(2 in the dinethylformamide, 4-two fluoroanilino)-5-fluoro-6-(sym-trimethylbenzene sulfonyloxy) nicotinic acid methyl ester, in gained solution, add 1.34g thiophenol and 1.23g triethylamine, then, the gained mixture reacted under room temperature 5 hours.Then, in reaction mixture, add 120ml ethyl acetate and 120ml water, and the pH value of this mixture is adjusted to 2 with 2N hydrochloric acid.Tell organic layer, successively with 80ml water and the washing of 80ml saturated sodium-chloride water solution, then with anhydrous magnesium sulfate drying.Underpressure distillation removes and desolvates, and adds the 20ml normal hexane in the gained crystallisate, then, filters the crystallization that collecting precipitation goes out, and obtains 2.85g(productive rate 90.2%) 2-(2,4-two fluoroanilino)-5-fluoro-6-thiophenyl nicotinic acid methyl ester, m.p.126-128 ℃.The physical properties of this compound is identical with example 7 gained compounds.

With top same method, make 2-(2,4-two fluoroanilino)-6-ethylmercapto group-5-fluorine nicotinic acid methyl esters.The physical properties of this compound is identical with example 7 gained compounds.

Example 12

Suspension 3.00g 2-(2 in 30ml methyl alcohol, 4-two fluoroanilino-5-fluoro-6-hydroxy niacin methyl esters, and under room temperature, add the 16.1ml2N aqueous sodium hydroxide solution, then, the gained mixture reacted 4 hours under refluxing.Then, this reaction mixture is added in the mixture of 60ml ethyl acetate and 60ml water, divides water-yielding stratum.PH value to 1.0 with 6N hydrochloric acid adjusting water layer filters the crystallization that collecting precipitation goes out, and uses 15ml water and 15ml washed with isopropyl alcohol successively, obtains 2.68g(productive rate 93.7%) 2-(2,4-two fluoroanilino)-5-fluoro-6-hydroxy niacin, m.p.213-216 ℃

M.p.:215-216 ℃ (acetone-ethanol (volume ratio 1: 1) recrystallization)

IR（KBr）Cm ^-1：νc＝0 ¹⁷⁰⁰

NMR(DMSO-d ₆) the δ value:

6.65-7.58（2H，m），7.86（1H，d，J＝11Hz），

8.12-8.68（1H，m），10.49（1H，bs）

Make 5-fluoro-2-(4-fluoroanilino with top same method)-the 6-hydroxy niacin.

M.p.:216-217 ℃ (acetone-methyl alcohol (volume ratio 1: 1), recrystallization)

IR（KBr）Cm ^-1：νc＝0 ^1685（sh）

NMR(DMSO-d ₆) the δ value:

6.84-7.94（5H，m），10.33（1H，bs）

Example 13

Dissolving 200g 2-(2 in the 60ml tetrahydrofuran (THF), 4-two fluoroanilino)-5-fluoro-6-methoxyl group nicotinic acid methyl ester, and under room temperature, add 25.5ml 1N aqueous sodium hydroxide solution, then, this mixture reacted 7 hours under refluxing.Then, underpressure distillation removes and desolvates, and adds 100ml ethyl acetate and 100ml water in the gained resistates, then, with 2N hydrochloric acid the gained mixture is transferred to pH2.0.Organic layer is successively with 50ml water and the washing of 50ml saturated sodium-chloride water solution, anhydrous magnesium sulfate drying.Underpressure distillation removes and desolvates, and adds the 10ml ether in the gained crystallisate, then, filters and collects crystallization, obtains 1.40g(productive rate 73.3%) 2-(2,4-two fluoroanilino)-5-fluoro-6-methoxyl group nicotinic acid, m.p.237-240 ℃.

M.p.:239-240 ℃ (acetone recrystallization)

IR（KBr）Cm ^-1：ν _C＝0 ¹⁶⁶⁵

NMR(DMSO-d ₆) the δ value:

3.98（3H，s），6.76-7.48（2H，m），7.86（1H，d，J＝11Hz），8.10-8.60（1H，m），10.51（1H，bs）

With top identical method, make following compound;

O 6-chloro-2-(2,4-two fluoroanilino)-the 5-fluorine nicotinic acid

M.p.:226-228 ℃ (benzene recrystallization)

IR（KBr）Cm ^-1：ν _C＝0 ¹⁶⁸⁰

NMR(acetone-d ₆) the δ value:

10.30（1H，bs），10.64（1H，bs）

O 2-(2,4-two fluoroanilino)-5-fluoro-6-(2,4,6-trimethylbenzene sulfonyloxy) nicotinic acid

M.p.:179-180 ℃ (benzene recrystallization)

IR（KBr）cm ^-1：ν _C＝0 ¹⁶⁶⁵

NMR(acetone-d ₆) the δ value:

10.37（1H，bs）

O 2-(2,4-two fluoroanilino)-5-fluoro-6-(2,4,6-tri isopropyl benzenesulfonyl oxygen base) nicotinic acid

M.p.:163.5-164.5 ℃ (benzene recrystallization)

IR（KBr）cm ^-1ν _C＝0 1675

NMR(

) the δ value:

1.22（12H，d，J＝7Hz），1.30（6H，d，J＝7Hz）

2.55-3.30（1H，m），3.70-4.40（2H，m），

9.66（1H，bs），10.57（1H，bs）

O 6-ethylmercapto group-2-(2,4-two fluoroanilino)-the 5-fluorine nicotinic acid

M.p.:209-210 ℃ (benzene recrystallization)

IR（KB _r）cm ^-1：ν _C＝0 ¹⁶⁶⁵

NMR(acetone-d ₆) the δ value:

1.3（3H，t，J＝7Hz）3.14（2H，q，J＝7Hz）

9.70（1H，bs），10.27（1H，bs）

O 2-(2,4-two fluoroanilino)-5-fluoro-6-thiophenyl nicotinic acid

M.p.:264-265 ℃ (ethyl acetate-ethanol (volume ratio 1: 1) recrystallization)

IR（KBr）cm ^-1：ν _C＝0 ¹⁶⁶⁰

NMR(DMSO-d ₆) the δ value:

6.00-7.73（8H，m），7.85（1H，d，J＝10Hz）

10.58（1H，bs）

Example 14

In the 30ml tetrahydrofuran (THF), suspension 980mg6-(3-acetylaminohydroxyphenylarsonic acid 1-pyrrolidyl in the mixture of 10ml methyl alcohol and 4ml water)-and 2-(2,4-two fluoroanilino)-5-fluorine nicotinic acid methyl esters, and add 5.3ml 1N aqueous sodium hydroxide solution, then, the gained mixture reacted 3 hours down in 65 ℃.Then, this reaction mixture is added in the mixture of 50ml ethyl acetate and 50ml water, is adjusted to pH2 with 1N hydrochloric acid.Filter the crystallization that collecting precipitation goes out and use 2ml water and 2ml washing with alcohol successively, obtain 880mg(productive rate 93.0%) 6-(3-acetylaminohydroxyphenylarsonic acid 1-pyrrolidyl)-2-(2,4-two fluoroanilino-5-fluorine nicotinic acid, m, p, 232-234 ℃.

M.p.:233.5-236 ℃ (acetone-methyl alcohol (volume ratio 1: 1) recrystallization)

IR（KB _r）cm ^-1：ν _C＝0 ¹⁶⁴⁵

NMR(TFA-d ₁) the δ value:

6.82-7.80（3H，m），8.27（1H，d，J＝13Hz）

With top same method, obtain 6-(4-ethanoyl-1-piperazinyl)-2-(2,4-two fluoroanilino)-the 5-fluorine nicotinic acid.

M.p.:243-244 ℃ of (ethyl acetate-ethanol (volume ratio 1: 1)

Recrystallization)

IR（KB _r）Cm ^-1：νc＝0 ^{1670，1635（sh）}

NMR(TFA-d ₁) the δ value:

2.48（3H，s），3.47-4.40（8H，m），

6.83-7.82（3H，m），8.47（1H，d，J＝13Hz）

Example 15

Suspension 130mg6-(4-ethanoyl-1-piperazinyl in 3.9ml methyl alcohol)-and 2-(2,4-two fluoroanilino)-5-fluorine nicotinic acid methyl esters, and add 3.33ml 2N aqueous sodium hydroxide solution, then, this mixture reacted 2 hours under refluxing.Add 2ml water in this reaction mixture, then, be adjusted to pH8.5 with 1N hydrochloric acid, filter the crystallization that collecting precipitation goes out,, obtain 110mg(productive rate 98.2% with the 2ml water washing) 2-(2,4-two fluoroanilino)-and 5-fluoro-6-(1-piperazinyl) nicotinic acid, m.p.279-281 ℃.

IR（KB _r）cm ^-1：νc＝0 ^1625（sh）

NMR(TFA-d ₁) the δ value:

3.53-4.33（8H，m），6.87-7.77（3H，m），

8.53（1H，d，J＝13Hz）

With top identical method, obtain 6-(3-amino-1-pyrrolidyl)-2-(2,4-two fluoroanilino)-the 5-fluorine nicotinic acid.

m.p.：249-250℃。

IR（KBr）Cm ^-1：νc＝0 ^1630（sh）

NMR(TFA-d ₁) the δ value:

2.47-2.92（2H，m），3.72-4.23（2H，m）

4.23-4.73（3H，m），6.95-7.77（3H，m），

8.36（1H，d，J＝13Hz）

Example 16

The 5.00g2-(2 that in the 150ml methylene dichloride, suspends, 4-two fluoroanilino)-and 5-fluoro-6-methoxyl group nicotinic acid, and add 5.98g thionyl chloride and 3 N, dinethylformamide, then, the reaction 2 hours under refluxing of this mixture.Underpressure distillation removes desolvates and excessive thionyl chloride, adds the 10ml normal hexane in the gained crystallisate, then, filters and collects crystallization, obtains 4.87g(productive rate 91.7%) 2-(2,4-two fluoroanilino)-5-fluoro-6-methoxyl group nicotinoyl chlorine, m.p.153-154 ℃.

M.p.:154-155 ℃ (methylene dichloride recrystallization)

IR（KB _r）Cm ^-1：νc＝0 ¹⁶⁸⁰

NMR(CDCl ₃) the δ value:

3.98（3H，s），6.60-7.10（2H，m），

With top same method, obtain compound shown in the table 3.

Example 17

In the 10ml methylene dichloride, dissolve 500mg2-(2,4-two fluoroanilino)-and 5-fluoro-6-(sym-trimethylbenzene sulfonyloxy) nicotinoyl chlorine, and under-20 ℃, drip the 1ml dichloromethane solution that contains 77mg imidazoles and 120mg triethylamine, then, this mixture reacted under room temperature 30 minutes.Then, in reaction mixture, add 5ml water, and regulate pH to 2.0 with 2N hydrochloric acid.Tell organic layer, successively with 5ml water and the washing of 5ml saturated sodium-chloride water solution, anhydrous magnesium sulfate drying.Underpressure distillation removes and desolvates, and adds the 2ml diisopropyl ether in the gained crystallisate, then; filter and collect crystallization, obtain 485mg(productive rate 91.1%) 1-(2-(2,4-two fluoroanilino)-5-fluoro-6-(sym-trimethylbenzene sulfonyloxy) nicotinoyl) imidazoles; mp, 98-101 ℃.

M.p.:103-105 ℃ (diisopropyl ether-ether (volume ratio 1: 1) recrystallization)

IR（KB _r）cm ^-1：ν _C＝0 ¹⁶⁷⁰

NMR(CDCl ₃) the δ value:

2.33（3H，s），2.60（6H，s），

6.35-8.15（9H，m），9.60（1H，bs）

With top same method, obtain the compound shown in the table 4.

Example 18

In the 7ml anhydrous tetrahydro furan, dissolve 200mg2-(2,4-two fluoroanilino)-5-fluoro-6-methoxyl group nicotinoyl chlorine, in-the 20--10 ℃ 1ml anhydrous tetrahydro furan that following dropping contains 45mg imidazoles and 65mg triethylamine is in this solution, and then, reaction is 30 minutes under room temperature.Then, at room temperature add 150mg ethoxycarbonyl magnesium acetate, and under refluxing, reacted 30 minutes, then, reaction mixture is added in the mixture of 10ml ethyl acetate and 10ml water, regulate this mixture to pH2.0 with 2N hydrochloric acid.Tell organic layer, add 5ml water, then, be adjusted to pH7.5 with saturated sodium bicarbonate aqueous solution.Tell organic layer, successively with 5ml water and the washing of 5ml saturated sodium-chloride water solution, anhydrous magnesium sulfate drying.Underpressure distillation removes and desolvates, and adds the 1ml diisopropyl ether in the gained crystallisate, then, filters the collection crystallization and obtains 190mg(productive rate 81.7%) 2-(2-(2,4-two fluoroanilino)-5-fluoro-6-methoxyl group nicotinoyl) ethyl acetate, m.p.148-149 ℃.

M.p:149-150 ℃ (benzene recrystallization)

IR（KB _r）cm ^-1：ν _C＝0 ¹⁷⁴⁵

NMR(CDCl ₃) the δ value:

1.30（3H，t，J＝7Hz），3.90（2H，s），4.02（3H，s），

4.27（2H，q，J＝7Hz），6.65-7.35（2H，m），

7.73（1H，d，J＝10Hz），7.90-8.40（1H，m），

11.19（1H，bs）

Example 19

Repeat example 16 and 18 same methods, obtain compound shown in the table 5.

Example 20

In the 4ml anhydrous tetrahydro furan, dissolve 200mg1-(2-(2,4-two fluoroanilino)-5-fluoro-6-(sym-trimethylbenzene sulfonyloxy) nicotinoyl) imidazoles, and add 90mg ethoxycarbonyl magnesium acetate, and then, in 50-60 ℃ of reaction 20 minutes.Then, this reaction mixture is added in the mixture of 10ml ethyl acetate and 10ml water, and is adjusted to PH2.0 with 2N hydrochloric acid.Tell organic layer, successively with 5ml water and the washing of 5ml saturated sodium-chloride water solution, anhydrous magnesium sulfate drying.Underpressure distillation removes and desolvates, and adds the 1ml ether in the gained crystallisate, then, filters and collects crystallization, obtains 175mg(productive rate 84.2%) 2-(2-(2,4-two fluoroanilino)-5-fluoro-6-(sym-trimethylbenzene sulfonyloxy) nicotinoyl) ethyl acetate.The physical properties of this compound is identical with example 19 gained compounds.

With top same method, obtain following compounds.

O 2-(2-(2,4-two fluoroanilino)-5-fluoro-6-methoxy nicotinoyl) ethyl acetate

O 2-(2-(2,4-two fluoroanilino)-6-ethylmercapto group-5-fluorine nicotinoyl) ethyl acetate

O 2-(2-(2,4-two fluoroanilino)-5-fluoro-6-thiophenyl nicotinoyl) ethyl acetate

The physical properties of these compounds is identical with the respective compound of example 18 and 19 gained.

Example 21

Suspension 930mg6-(3-acetylaminohydroxyphenylarsonic acid 1-pyrrolidyl in the 37ml anhydrous tetrahydro furan)-2-(2,4-two fluoroanilino)-the 5-fluorine nicotinic acid, and under the ice bath cooling, add 760mgN, N '-carbonyl dimidazoles, then, the gained mixture reacted under room temperature 12 hours.Then, add 670mg ethoxycarbonyl magnesium acetate, and reacted 2 hours down in 60 ℃.Reaction mixture is added in the mixture of 100ml ethyl acetate and 50ml water, and is adjusted to PH2.0, then, tell organic layer with 2N hydrochloric acid.In organic layer, add 50ml water and be adjusted to PH7.0 with saturated sodium bicarbonate aqueous solution.Tell organic layer, successively with 50ml water and the washing of 50ml saturated sodium-chloride water solution, anhydrous magnesium sulfate drying.Underpressure distillation removes and desolvates; the gained resistates is by column chromatography purification (WaKo silica gel C-200; eluent: chloroform-ethanol (volume ratio is 200: 1)); obtain 610mg(productive rate 55.7%) 2-(6-(3-acetylaminohydroxyphenylarsonic acid 1-pyrrolidyl)-2-(2; 4-two fluoroanilino)-and 5-fluorine nicotinoyl) ethyl acetate, m.p.182-184 ℃.

Example 22

(1) suspension 2.34g 2-(2 in the 94ml anhydrous tetrahydro furan, 4-two fluoroanilino)-5-fluoro-6-hydroxy niacin, and under the ice bath cooling, add 2.00gN, N '-carbonyl dimidazoles, gained mixture reacted under room temperature 2 hours.Then, in this reaction mixture, add 3.50g ethoxycarbonyl magnesium acetate, and, then, this reaction mixture is added in the mixture of 150ml ethyl acetate and 150ml water, and is adjusted to pH2.0 with 6N hydrochloric acid in the reaction down 1.5 hours that refluxes.Tell organic layer, use 80ml saturated sodium bicarbonate aqueous solution and 80ml water washing successively, add 80ml water then and be adjusted to pH2.0 with 6N hydrochloric acid.Tell organic layer; successively with 80ml water and the washing of 80ml saturated sodium-chloride water solution; then, use anhydrous magnesium sulfate drying, underpressure distillation removes and desolvates; and in the gained crystallisate, add the 8ml ether; then, filter and collect crystallization, obtain 1.93g(productive rate 66.2%) 2-(2-(2; 4-two fluoroanilino)-and 5-fluoro-6-hydroxyl nicotinoyl) ethyl acetate, m.p.161-162 ℃.

M.p.:161.5-162 ℃ (benzene recrystallization)

IR（KB _r）cm ^-1：ν _C＝0 ^1725，1665

NMR(CDCl ₃) the δ value:

1.29（3H，t，J＝7Hz），3.74（2H，s），4.20（2H，q，

J＝7Hz），6.57-7.69（4H，m），10.17（1H，bs），

11.52（1H，bs）

With top same method, obtain 2-(5-fluoro-2-(4-fluoroanilino)-6-hydroxyl nicotinoyl) ethyl acetate.

M.p.:185 ℃ of (decomposition) (re-crystallizing in ethyl acetate)

IR（KBr）cm ^-1ν _C＝0 ^1715，1685

NMR(CDCl ₃) the δ value:

1.30（3H，t，J＝7Hz），3.75（2H，s），4.25（2H，q，

J＝7Hz），7.08-7.34（4H，m），7.48（1H，d，

J＝11Hz）

11.86（1H，bs）

(2) repeat above the method for (1), but temperature of reaction and reaction times be respectively 60 ℃ and 3 hours, obtain 2-(2-(2,4-two fluoroanilino)-5-fluoro-6-hydroxyl nicotinoyl) ethyl acetate, productive rate 34.5%.

Example 23

Dissolving 700mg6-chloro-2-(2 in the 30ml anhydrous tetrahydro furan, 4-two fluoroanilino)-the 5-fluorine nicotinic acid, and under the ice bath cooling, add 1.13gN, N '-carbonyl dimidazoles, gained mixture reacted under room temperature 6 hours.Then, add 990mg ethoxycarbonyl magnesium acetate, the gained mixture reacted 2 hours down in 55 ℃, then, this reaction mixture was added in the mixture of 75ml ethyl acetate and 65ml water.Be adjusted to pH2.0 with 6N hydrochloric acid.Tell organic layer, add 30ml water, then, be adjusted to pH7.5 with saturated sodium bicarbonate aqueous solution.Tell organic layer, successively with 30ml water and the washing of 30ml saturated sodium-chloride water solution, anhydrous magnesium sulfate drying.Underpressure distillation removes and desolvates, and the gained resistates is through column chromatography purification (WaKo silica gel C-200, eluent: benzene), obtain 680mg(productive rate 78.9%) 2-(6-chloro-2-(2,4-two fluoroanilino)-5-fluorine nicotinoyl) ethyl acetate.The physical properties of this compound is identical with example 19 gained compounds.

With top same method, obtain following compounds:

O 2-(2-(2,4-two fluoroanilino)-5-fluoro-6-methoxyl group nicotinoyl) ethyl acetate

O 2-(2-(2,4-two fluoroanilino)-6-ethylmercapto group-5-fluorine nicotinoyl) ethyl acetate

O 2-(2-(2,4-two fluoroanilino)-5-fluoro-6-thiophenyl nicotinoyl) ethyl acetate

O 2-(2-(2,4-two fluoroanilino)-5-fluoro-6-(2,4,6-Three methyl Benzene sulfonyloxy) nicotinoyl) ethyl acetate

O 2-(6-(4-ethanoyl-1-piperazinyl)-2-(2,4-two fluoroanilino)-5-fluorine nicotinoyl) ethyl acetate

The physical properties of these compounds is identical with 19 gained respective compound with example 18.

Example 24

(1) suspension 280mg 2-(2 in the 3ml methylene dichloride, 4-two fluoroanilino)-5-fluoro-6-methoxyl group nicotinic acid, and under room temperature, add 580mg thionyl chloride and 1 N, dinethylformamide, the gained mixture is in the reaction down 2 hours that refluxes.Underpressure distillation removes desolvates and excessive thionyl chloride, and the gained crystallisate is dissolved in the 6ml methylene dichloride.

(2) dissolving 590mg propanedioic acid diphenyl-methyl ethyl ester in the 6ml anhydrous tetrahydro furan, and in-20 ℃ of following 90mg sodium hydride (purity: 50%) that add, the gained mixture was in 0-10 ℃ of reaction 1 hour, then, reaction mixture is chilled to-20 ℃, and the dichloromethane solution of (1) gained above under this temperature, dripping, then, the gained mixture reacted 30 minutes down in-20--10 ℃.Add 120mg acetate in reaction mixture, underpressure distillation removes and desolvates, and then, adds 20ml ethyl acetate and 10ml water in the gained resistates.Be adjusted to pH2.0 with 2N hydrochloric acid.Tell organic layer, successively with 10ml water and the washing of 10ml saturated sodium-chloride water solution, anhydrous magnesium sulfate drying.Underpressure distillation removes and desolvates, and adds the 5ml diisopropyl ether in the gained resistates, filters and collects crystallization, obtains 430mg(productive rate 79.2%) 2-(2,4-two fluoroanilino)-5-fluoro-6-methoxyl group nicotinoyl propanedioic acid diphenyl-methyl ethyl ester.

M.p.:130-131 ℃ (recrystallization in benzene-normal hexane (volume ratio 1: 1))

IR（KBr）cm ^-1：ν _C＝0 ^{1740，1730（sh）}

NMR(CDCl ₃) the δ value:

1.24（3H，t，J＝7Hz），3.94（3H，s），4.28（2H，q，

J＝7Hz），5.14（1H，s），6.40-7.64（14H，m），

7.70-8.20（1H，m），11.10（1H，bs）

(3) in the 2ml methyl-phenoxide, dissolve 200mg2-(2,4-two fluoroanilino)-5-fluoro-6-methoxyl group nicotinoyl propanedioic acid diphenyl-methyl ethyl ester, and in the ice bath cooling down, add the 2ml trifluoroacetic acid, the gained mixture reacted 10 minutes under same temperature.Underpressure distillation removes and desolvates, and adds the 2ml diisopropyl ether in the gained crystallisate.Then, filter and collect crystallization, obtain 120mg(productive rate 94.3%) 2-(2-(2,4-two fluoroanilino)-5-fluoro-6-methoxyl group nicotinoyl) ethyl acetate.

The physical properties of this compound is identical with example 18 gained compounds.

Example 25

In the 2ml ethyl acetate, dissolve 100mg2-(2-(2,4-two fluoroanilino)-5-fluoro-6-hydroxyl nicotinoyl) ethyl acetate, and under the ice bath cooling, add the diethyl ether solution that contains the 15mg diazomethane, the gained mixture reacted under room temperature 30 minutes.Then, adding acetate is non-foaming in reaction mixture in reaction mixture.Underpressure distillation removes and desolvates, and adds the 2ml diisopropyl ether in the gained crystallisate, then, filters and collects crystallization, obtains 80mg(productive rate 77.0%) 2-(2-(2,4-two fluoroanilino)-5-fluoro-6-methoxyl group nicotinoyl) ethyl acetate.The physical properties of this compound is identical with example 18 gained compounds.

Example 26

In the 4ml methylene dichloride, dissolve 400mg2-(2-(2; 4-two fluoroanilino)-and 5-fluoro-6-hydroxyl nicotinoyl) ethyl acetate, and under the ice bath cooling, add 300mg2,4; 6-trimethylbenzene chloride and 150mg triethylamine, gained mixture reacted under room temperature 2 hours.Then, in this reaction mixture, add 4ml methylene dichloride and 4ml water, tell organic layer, successively with 4ml water and the washing of 4ml saturated sodium-chloride water solution, anhydrous magnesium sulfate drying.Underpressure distillation removes and desolvates, and adds the 2ml ether in the gained crystallisate, then, filters and collects crystallization, obtains 520mg(productive rate 85.8%) 2-(2-(2,4-two fluoroanilino)-5-fluoro-6-(2,4,6-Three methyl Benzene sulfonyloxy) nicotinoyl) ethyl acetate.The physical properties of this compound is identical with example 19 gained compounds.

With top same method, obtain following compound:

O 2-(2-(2,4-two fluoroanilino)-5-fluoro-6-mesyloxy nicotinoyl) ethyl acetate

M.p.:98-99 ℃ (benzene recrystallization)

IR（KBr）cm ^-1：ν _C＝0 ¹⁷³⁰

NMR(CDCl ₃) the δ value:

1.27（3H，t，J＝7Hz），3.28（3H，s），3.93（2H，s），

4.23（2H，q，J＝7Hz），6.63-7.43（2H，m），

O 2-(2-(2,4-two fluoroanilino)-5-fluoro-6-(2,4,6-tri isopropyl benzenesulfonyl oxygen base) nicotinoyl) ethyl acetate

The physical properties of this compound is identical with example 19 gained compounds.

Example 27

In 1.5ml N, dissolving 150mg 2-(6-chloro-2-(2,4-two fluoroanilino)-5-fluorine nicotinoyl in the dinethylformamide) ethyl acetate, and add 70mg thiophenol and 60mg triethylamine, the gained mixture reacted under room temperature 1 hour.Then, in this reaction mixture, add 20ml ethyl acetate and 10ml water, and be adjusted to pH2.0 with 2N hydrochloric acid.Tell organic layer, successively with 10ml water and the washing of 10ml saturated sodium-chloride water solution, anhydrous magnesium sulfate drying.Underpressure distillation removes and desolvates, and adds the 5ml normal hexane in the gained crystallisate, then, filters and collects crystallization, obtains 170mg(productive rate 94.6%) 2-(2-(2,4-two fluoroanilino)-5-fluoro-6-thiophenyl nicotinoyl) ethyl acetate.The physical properties of this compound is identical with example 19 gained compounds.

Example 28

At 1ml N, dissolving 100mg 2-(2-(2,4-two fluoroanilino)-5-fluoro-6-(2 in the dinethylformamide; 4,6-Three methyl Benzene sulfonyloxy) nicotinoyl) ethyl acetate, then; add 17mg sulfur alcohol and 28mg triethylamine, the gained mixture reacted under room temperature 4 hours.Then, in this reaction mixture, add 3ml ethyl acetate and 3ml water, and be adjusted to pH1.0 with 2N hydrochloric acid.Tell organic layer, successively with 2ml water and the washing of 2ml saturated sodium-chloride water solution, and with anhydrous magnesium sulfate drying.Underpressure distillation removes and desolvates; the gained resistates is through column chromatography purification (WaKo silica gel C-200; eluent: benzene-normal hexane (volume ratio 1: 2)) obtain 50mg(productive rate 67.4%) ethyl acetate 2-(2-(2,4-two fluoroanilino)-6-ethylmercapto group-5-fluorine nicotinoyl).The physical properties of this compound is identical with example 19 gained compounds.

With above-mentioned same method, obtain 2-(2-(2,4-two fluoroanilino)-5-fluoro-6-thiophenyl nicotinoyl) ethyl acetate.The physical properties of this compound is identical with example 19 gained compounds.

Example 29

Dissolving 500mg 2-(6-chloro-2-(2 in the 5ml chloroform; 4-two fluoroanilino)-and 5-fluorine nicotinoyl) ethyl acetate; and add 260mg 3-amino-pyrrolidine dihydrochloride and 500mg triethylamine, then, the gained mixture reacted 1.5 hours under refluxing.Then, this reaction mixture is added in the mixture of 5ml chloroform and 5ml water, tells organic layer, successively with 5ml water and the washing of 5ml saturated sodium-chloride water solution, and with anhydrous magnesium sulfate drying.Underpressure distillation removes and desolvates, and adds the 2ml diisopropyl ether in the gained crystallisate, then; filter and collect crystallization; obtain 480mg(productive rate 84.7%) 2-(6-(3-amino-1-pyrrolidyl)-2-(2,4-two fluoroanilino)-5-fluorine nicotinoyl) ethyl acetate, mp.140-142 ℃.

IR（KBr）cm ^-1：ν _C＝o ¹⁷³⁰

NMR(DMSO-d ₆) the δ value:

1.22（3H，t，J＝7Hz），1.50-2.30（2H，m），

3.30-4.40（9H，m），6.80-7.60（2H，m），

7.81（1H，d，J＝14Hz），8.00-8.70（1H，m），

11.45（1H，bs）

Example 30

Dissolving 140mg Piperazine anhydrous in 1.5ml ethanol, and in gained solution, add 150mg2-(6-chloro-2-(2,4-two fluoroanilino)-5-fluorine nicotinoyl in batches) ethyl acetate, the gained mixture reacted under room temperature 30 minutes.Then, this reaction mixture is added in the mixture of 5ml chloroform and 5ml water, tells organic layer, successively with 3ml water and the washing of 3ml saturated sodium-chloride water solution, and with anhydrous magnesium sulfate drying.Underpressure distillation removes and desolvates, and adds the 2ml normal hexane in the gained crystallisate, then, filters and collects crystallization, obtains 70mg(productive rate 41.2%) 2-(2-(2,4-two fluoroanilino)-5-fluoro-6-(1-piperazinyl) nicotinoyl) ethyl acetate.

M.p.:121-123 ℃ of (ethyl acetate-normal hexane (volume ratio is 10: 1)

Recrystallization)

IR（KBr）cm ^-1：ν _C＝o 1745，1730（sh）

NMR(CDCl ₃) the δ value:

1.30（3H，t，J＝7Hz），2.76-3.10（4H，m）

3.55-4.00（6H，m），4.21（2H，q，J＝7Hz）

6.40-7.20（2H，m），7.47（1H，d，J＝14Hz）

7.75-8.35（1H，m），11.10（1H，bs）

Example 31

Suspension 50mg3-amino-pyrrolidine dihydrochloride in the 1.5ml chloroform, and add the 110mg triethylamine, the gained mixture reacted under room temperature 10 minutes.Then, add 150mg2-(2-(2,4-two fluoroanilino)-5-fluoro-6-(2,4,6-Three methyl Benzene sulfonyloxy) nicotinoyl) ethyl acetate.The gained mixture reacted under room temperature 1.5 hours.Then, add 5ml chloroform and 5ml water, tell organic layer, successively with 5ml water and the washing of 5ml saturated sodium-chloride water solution, and with anhydrous magnesium sulfate drying.Underpressure distillation removes and desolvates, and adds the 2ml diisopropyl ether in the gained crystallisate, then, filters and collects crystallization, obtains 110mg(productive rate 93.2%) 2-(6-(3-amino-1-pyrrolidyl)-2-(2,4-two fluoroanilino)-5-fluorine nicotinoyl) ethyl acetate.The physical properties of this compound is identical with example 29 gained compounds.

Example 32

Dissolving 130mg Piperazine anhydrous in the 2ml methylene dichloride; under the ice bath cooling, add 200mg2-(2-(2,4-two fluoroanilino)-5-fluoro-6-(2,4; 6-Three methyl Benzene sulfonyloxy) ethyl acetate nicotinoyl); then, the gained mixture reacted 40 minutes under same temperature, then; in this reaction mixture, add 10ml ethyl acetate and 10ml water; tell organic layer, successively with 2ml saturated sodium bicarbonate aqueous solution and the washing of 2ml saturated sodium-chloride water solution, anhydrous magnesium sulfate drying.Underpressure distillation removes and desolvates, and adds the 1ml normal hexane in the gained crystallisate, then, filters and collects crystallization, obtains 110mg(productive rate 69.9%) 2-(2-(2,4-two fluoroanilino)-5-fluoro-6-(1-piperazinyl) nicotinoyl) ethyl acetate.The physical properties of this compound is identical with example 30 gained compounds.

Example 33

In the 1ml chloroform, dissolve 100mg2-(6-(3-amino-1-pyrrolidyl) 2-(2,4-two fluoroanilino)-5-fluorine nicotinoyl) ethyl acetate, and add the 26mg diacetyl oxide, then, the gained mixture reacted under room temperature 30 minutes.Then, this reaction mixture is added in the mixture of 1ml water and 1ml chloroform and goes, tell organic layer, successively with 1ml water and the washing of 1ml saturated sodium-chloride water solution, and with anhydrous magnesium sulfate drying.Underpressure distillation removes and desolvates; add the 0.5ml diisopropyl ether in the gained crystallisate, then, filter and collect crystallization; obtain 80mg(productive rate 72.8%) 2-(6-(3-acetylaminohydroxyphenylarsonic acid 1-pyrrolidyl)-2-(2,4-two fluoroanilino)-5-fluorine nicotinoyl) ethyl acetate.The physical properties of this compound is identical with example 19 gained compounds.

With above-mentioned identical method, obtain 2-(6-(4-ethanoyl-1-piperazinyl)-2-(2,4-two fluoroanilino)-5-fluorine nicotinoyl) ethyl acetate.The physical properties of this compound is identical with example 19 gained compounds.

Example 34

In 58ml N; dissolving 5.80g 2-(2-(2 in the dinethylformamide; 4-two fluoroanilino)-5-fluoro-6-(2; 4; 6-tri isopropyl benzenesulfonyl oxygen base) ethyl acetate nicotinoyl); and add 1.24g thiophenol and 1.23g triethylamine, then, the gained mixture reacted under room temperature 4 hours.Then, in this reaction mixture, add 400ml ethyl acetate and 200ml water, then, be adjusted to pH2.0 with 2N hydrochloric acid.Tell organic layer, successively with 200ml water and the washing of 200ml saturated sodium-chloride water solution, and with anhydrous magnesium sulfate drying.Underpressure distillation removes and desolvates, and adds the 50ml normal hexane in the gained crystallisate, filters and collects crystallization, obtains 3.99g(productive rate 95.6%) 2-(2-(2,4-two fluoroanilino)-5-fluoro-6-thiophenyl nicotinoyl) ethyl acetate.The physical properties of this compound is identical with example 19 gained compounds.

With above-mentioned identical method, obtain 2-(2-(2,4-two fluoroanilino)-6-ethylmercapto group-5-fluorine nicotinoyl) ethyl acetate.The physical properties of this compound is identical with example 19 gained compounds.

Example 35

1.00g2-(2-(2 suspends in the 10ml anhydrous acetonitrile; 4-two fluoroanilino)-and 5-fluoro-6-hydroxyl nicotinoyl) ethyl acetate; and under the ice bath cooling, add 390mg triethylamine and 670mg diethylchlorophosphate (C2H5O)2P(O)Cl, then, the gained mixture reacted under room temperature 1.5 hours.Add 50ml methylene dichloride and 50ml water in this reaction mixture, tell organic layer, wash four times, each 50ml is with anhydrous magnesium sulfate drying.Underpressure distillation removes and desolvates, and adds the 15ml normal hexane in the gained resistates, then; filter and collect crystallization; obtain 1.26g(productive rate 91.0%) 2-(6-diethoxy phosphoryl oxy-2-(2,4-two fluoroanilino)-5-fluorine nicotinoyl) ethyl acetate, m.p.127-130 ℃.

M.p.:131.5-133 ℃ (benzene recrystallization)

IR（KBr）cm ^-1：νc＝0 1740

NMR(CDCl ₃) the δ value:

1.30（3H，t，J＝7Hz），1.33（3H，t，J＝7Hz），

1.35（3H，t，J＝7Hz），3.95（2H，s），

4.15（2H，q，J＝7Hz），4.25（2H，q，J＝7Hz），

4.30（2H，q，J＝7Hz），6.65-7.35（2H，m），

7.96（1H，d，J＝9Hz），8.15-8.75（1H，m），

11.05（1H，bs）

With above-mentioned same method, obtain 2-(2-(2,4-two fluoroanilino)-6-two phenoxy group phosphorus acyloxy-5-fluorine nicotinoyl) ethyl acetate.

M.p.:85-86 ℃ (ether recrystallization)

IR（KBr）cm ^-1：ν _C＝0 ¹⁷⁴⁰

NMR(CDCl ₃) the δ value:

1.25（3H，t，J＝7Hz），3.90（2H，s），

7.75-8.55（2H，m），11.07（1H，bs）

Example 36

In the 14ml methylene dichloride, dissolve 1.40g2-(2-(2; the 4-fluoroanilino)-and 6-ethylmercapto group-5-fluorine nicotinoyl) ethyl acetate; and (purity: 80%), then, the gained mixture reacted under room temperature 3 hours to add the 1.59g metachloroperbenzoic acid under the ice bath cooling.The elimination precipitation adds 10ml water in gained filtrate, then, be adjusted to pH7.5 with saturated sodium bicarbonate aqueous solution.Tell organic layer, successively with 10ml water and the washing of 10ml saturated sodium-chloride water solution, anhydrous magnesium sulfate drying.Underpressure distillation removes and desolvates, and adds the 10ml ether in the gained resistates, then; filter the crystallization that collecting precipitation goes out; obtain 1.28g(productive rate 84.6%) 2-(2-(2,4-two fluoroanilino)-6-ethylsulfonyl-5-fluorine nicotinoyl) ethyl acetate, m.p.113-114.5 ℃.

M.p.:114-115 ℃ (diisopropyl ether recrystallization)

IR（KBr）cm ^-1：ν _C＝o 1740

NMR(CDCl ₃) the δ value:

1.24（3H，t，J＝7Hz），1.27（3H，t，J＝7Hz），

3.27（2H，q，J＝7Hz），4.00（2H，s），

4.18（2H，q，J＝7Hz），6.55-7.10（2H，m），

With above-mentioned same method, obtain 2-(6-benzenesulfonyl-2-(2,4-two fluoroanilino)-5-fluorine nicotinoyl) ethyl acetate.

M.p.:140-141 ℃ (re-crystallizing in ethyl acetate)

IR（KBr）cm ^-1：ν _C＝o 1740

NMR(CDCl ₃) the δ value:

1.27（3H，t，J＝7Hz），4.01（2H，s），

4.21（2H，q，J＝7Hz），6.40-7.00（2H，m），

Example 37

Dissolving 2.0g 2-(2-(2 in the 20ml methylene dichloride; 4-two fluoroanilino)-and 5-fluoro-6-thiophenyl nicotinoyl) ethyl acetate; and (purity: 80%) then, the gained mixture reacted 5 hours under same temperature to add the 1.01g metachloroperbenzoic acid down in the ice bath cooling.Remove by filter precipitation, in gained filtrate, add 20ml water, then, be adjusted to pH7.5 with saturated sodium bicarbonate aqueous solution.Tell organic layer, with 20ml water washing, anhydrous magnesium sulfate drying.Underpressure distillation removes and desolvates, and the gained resistates is with column chromatography purification (W _aK _oSilica gel C-200, eluent: benzene-ethyl acetate (volume ratio 50: 1)), obtain 1.39g(productive rate 67.1%) 2-(6-benzenesulfinyl-2-(2,4-two fluoroanilino)-5-fluorine nicotinoyl) ethyl acetate, m.p.105-106.5 ℃.

M.p.:107-107.5 ℃ (diisopropyl ether recrystallization)

IR（KBr）cm ^-1：ν _C＝o 1730

NMR(CDCl ₃) the δ value:

1.25（3H，t，J＝7Hz），3.97（2H，s），

4.21（2H，q，J＝7Hz），6.60-8.00（8H，m），

8.30-8.85（1H，m），10.90（1H，bs）

With above-mentioned same method, obtain 2-(2-(2,4-two fluoroanilino)-6-second sulfinyl-5-fluorine nicotinoyl) ethyl acetate.

M.p.:115-116 ℃ (diisopropyl ether recrystallization)

IR（KB _r）cm ^-1：ν _C＝o 1735

NMR(CDCl ₃) the δ value:

1.29（3H，t，J＝7Hz），1.31（3H，t，J＝7Hz），

3.08（2H，q，J＝7Hz），4.03（2H，s），

4.23（2H，q，J＝7Hz），6.65-7.15（2H，m），

7.97（1H，d，J＝9Hz），8.40-9.00（1H，m），

10.88（1H，bs）

Example 38

1.05g2-(2-(2,4-two fluoroanilino)-5-fluoro-6-hydroxyl nicotinoyl suspends in the 10ml anhydrous acetonitrile) ethyl acetate, and under the ice bath cooling, add 450mg triethylamine and 1.22g diphenylphosphine acylazide.Then, the gained mixture reacted under room temperature 4 hours.In this reaction mixture, add 50ml ethyl acetate and 50ml water, tell organic layer, with anhydrous magnesium sulfate drying.Underpressure distillation removes and desolvates, and the gained resistates is with column chromatography purification (W _aK _oSilica gel C-200, eluent: benzene), obtain 550mg(productive rate 48.9%) 2-(6-azido--2-(2,4-two fluoroanilino)-5-fluorine nicotinoyl) ethyl acetate, m.p.130-131 ℃.

M.p.:130.5-131.5 ℃ (benzene recrystallization)

IR（KBr）cm ^-1：νN ₃2130，νc＝o 1750

NMR(CDCl ₃) the δ value:

1.29（3H，t，J＝7Hz），3.92（2H，s），

4.25（2H，q，J＝7Hz），6.60-8.45（4H，m），

10.94（1H，bs）

Example 39

200mg2-(6-(3-acetylaminohydroxyphenylarsonic acid 1-the pyrrolidyl)-2-(2 that in 2ml benzene, suspends, 4-two fluoroanilino)-5-fluorine nicotinoyl) ethyl acetate.And add 100mg N, and the dinethylformamide dimethyl acetal, then, the gained mixture reacted 7 hours under refluxing.Then, filter the crystallization that collecting precipitation goes out, obtain 180mg(productive rate 88.1% with the washing of 2ml ether) 7-(3-acetylaminohydroxyphenylarsonic acid 1-pyrrolidyl)-1-(2, the 4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester, m.p.233-236 ℃.

M.p.:234-236 ℃ (acetone-methyl alcohol (volume ratio 1: 1) recrystallization)

NMR(CDCl ₃) the δ value:

6.78-7.70（4H，m），8.10（1H，d，J＝8Hz），

8.31（1H，s）

With above-mentioned same method, obtain 7-(4-ethanoyl-1-piperazinyl)-1-(2,4-dioxy phenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester.

Productive rate: 84.2%.

M.p.:219-220 ℃ (acetone recrystallization)

Example 40

200mg2-(2-(2,4-two fluoroanilino)-5-fluoro-6-hydroxyl nicotinoyl suspends in 2ml benzene) ethyl acetate, and add 87mg N, and the dinethylformamide dimethyl acetal, then, the gained mixture is in the reaction down 10 hours that refluxes.Filter the crystallization that collecting precipitation goes out.In the gained crystallization, add 0.5ml methyl alcohol and 1ml water, and be adjusted to pH1.0 with 2N hydrochloric acid, then, filter the crystallization that collecting precipitation goes out, obtain 80mg(productive rate 38.9%) 1-(2, the 4-difluorophenyl)-6-fluoro-1,4-dihydro-7-hydroxyl-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester, m.p.243-248 ℃.

M.p.:250-252 ℃ (acetone-methyl alcohol (volume ratio is 1: 1) recrystallization)

IR（KBr）cm ^-1：ν _C＝o 1720

NMR(TFA-d ₁) the δ value:

1.51（3H，t，J＝7Hz），4.70（2H，q，J＝7Hz），

7.00-8.10（3H，m），8.30（1H，d，J＝8Hz），

9.11（1H，s）

With above-mentioned same method, obtain 6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-7-hydroxyl-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester.

M.p.:252-253 ℃ (acetone-methyl alcohol (volume ratio 1: 1) recrystallization)

IR（KBr）cm ^-1：ν _C＝o 1730（sh），1700

NMR(TFA-d ₁) the δ value:

1.50（3H，t，J＝7Hz），4.64（2H，q，J＝7Hz），

7.15-7.84（4H，m），8.20（1H，d，J＝9Hz），

9.02（1H，s）

Example 41

Suspension 200mg 2-in 4ml benzene (2-(2,4-two fluoroanilino)-5-fluoro-6-methoxyl group nicotinoyl) ethyl acetate, and add 71mgN, dinethylformamide dimethyl acetal.Then, the gained mixture reacted 9 hours under refluxing.Underpressure distillation removes and desolvates, and in the gained resistates, add the 2ml ether, then, filter the crystallization that collecting precipitation goes out, obtain 130mg(productive rate 63.3%) 1-(2, the 4-difluorophenyl)-6-fluoro-1,4-dihydro-7-methoxyl group-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester, m.p.190-192 ℃.

M.p.:193-194 ℃ (re-crystallizing in ethyl acetate)

IR（KB _r）cm ^-1：ν _C＝o 1730

NMR(CDCl ₃) the δ value:

1.38（3H，t，J＝7Hz），3.78（3H，s），

4.39（2H，q，J＝7Hz），6.82-7.82（3H，m），

8.22（1H，d，J＝9Hz），8.46（1H，s）

With above-mentioned same method, obtain the listed compound of table 6.

Example 42

Dissolving 160mg 2-(2-(2,4-two fluoroanilino)-6-ethylmercapto group-5-fluorine nicotinoyl in 3ml benzene) ethyl acetate, and add 72mg N, the dinethylformamide dimethyl acetal, then, the gained mixture is in the reaction down 2.5 hours that refluxes.Underpressure distillation removes and desolvates, the gained resistates is with column chromatography purification (WaKo silica gel C-200, eluent: benzene-ethyl acetate (volume ratio 10: 1)), obtain 115mg(productive rate 70.1%) 1-(2, the 4-difluorophenyl)-7-ethylmercapto group-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester, m.p:169.5-171 ℃.

M.p.:170-171 ℃ (re-crystallizing in ethyl acetate)

IR（KBr）cm ^-1：ν _C＝O ¹⁷³⁰

NMR(CDCl ₃) the δ value:

1.08（3H，t，J＝7Hz），1.38（3H，t，J＝7Hz），

2.79（2H，q，J＝7Hz），4.38（2H，q，J＝7Hz），

6.88-7.83（3H，m），8.10（1H，d，J＝9Hz），

8.48（1H，s）

With above-mentioned same method, obtain 1-(2, the 4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-7-thiophenyl-1,8-naphthyridine-3-carboxylic acid, ethyl ester.

M.p.:218.5-220 ℃ (acetone-methyl alcohol (volume ratio 1: 1) recrystallization)

IR（KBr）cm ^-1：ν _C＝O ^{1730，1700（sh）}

NMR(CDCl ₃) the δ value:

1.36（3H，t，J＝7Hz）4.33（2H，q，J＝7Hz），

8.33（1H，s）

Example 43

Suspension 200mg 2-in 4ml toluene (2-(2,4-two fluoroanilino)-5-fluoro-6-hydroxyl nicotinoyl) ethyl acetate, and add 200mg N, dinethylformamide two neopentyl alcohols that contract, then, the gained mixture reacted under room temperature 4 hours.Filter the crystallization that collecting precipitation goes out, and in this crystallization, add 5ml ethanol and 5ml water, then, be adjusted to pH1.0 with 2N hydrochloric acid.Filter and collect the gained crystallization, obtain 155mg(productive rate 75.4%) 1-(1, the 4-difluorophenyl)-6-fluoro-1,4-dihydro-7-hydroxyl-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester, m.p.244-248 ℃.The physical properties of this compound is identical with example 40 gained compounds.

With above-mentioned same method, obtain 6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-7-hydroxyl-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester, productive rate 72.8%.The physical properties of this compound is identical with example 40 gained compounds.

Example 44

(1) in the 6ml methylene dichloride, dissolves 300mg2-(2-(2; 4-two fluoroanilino)-5-fluoro-6-(2; 4; 6-Three methyl Benzene sulfonyloxy) ethyl acetate nicotinoyl); and adding 135mg N; dinethylformamide dimethyl acetal and 115mg diacetyl oxide, then, the gained mixture reacted under room temperature 30 minutes.In this reaction mixture, add 0.31ml 2N hydrochloric acid and 3ml ethanol, and under room temperature, reacted 1 hour, then, add 6ml methylene dichloride and 6ml water.Tell organic layer, with the washing of 6ml saturated sodium-chloride water solution, and with anhydrous magnesium sulfate drying.Underpressure distillation removes and desolvates, and in the gained crystallisate, add the 2ml diisopropyl ether, then, filter and collect crystallization, obtain 260mg(productive rate 85.1%) 1-(2, the 4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-7-(2,4,6-Three methyl Benzene sulfonyloxy)-1,8-naphthyridine-3-carboxylic acid, ethyl ester, m.p.170-173 ℃.The physical properties of this compound is identical with example 41 gained compounds.

With above-mentioned same method, obtain the listed compound of table 7.

(2) repeat top (1) described method, but with the listed N of table 8, the acetal of N-two substituted formamides replaces N, the dinethylformamide dimethyl acetal obtains the listed result of table 8.

Example 45

(1) in 4ml toluene, add 540mg(N, dinethylformamide-methyl-sulfate) coordination compound, and under 0 ℃, add the 85mg sodium methylate, then, the gained mixture was in 0-10 ℃ of reaction 1 hour.Then, in reaction mixture, add 200mg2-(2-(2,4-two fluoroanilino)-5-fluoro-6-methoxyl group nicotinoyl again) ethyl acetate, the gained mixture reacted 1.5 hours under refluxing.This reaction mixture is added in the mixture of 8ml ethyl acetate and 8ml water, tells organic layer, with the washing of 5ml saturated sodium-chloride water solution, anhydrous magnesium sulfate drying.Underpressure distillation removes and desolvates, and adds the 1ml ether in the gained crystallisate, then, filters and collects crystallization, obtains 170mg(productive rate 82.8%) 1-(2, the 4-difluorophenyl)-6-fluoro-1,4-dihydro-7-methoxyl group-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester.The physical properties of this compound is identical with example 41 gained compounds.

(2) repeat top (1) described method, still, replace (N, dinethylformamide-methyl-sulfate) coordination compound with (N-carbonyl pyrrolidine-methyl-sulfate) coordination compound, gained the results are shown in table 9

Example 46

In the 6ml methylene dichloride, add 335mg(N, dinethylformamide-methyl-sulfate) coordination compound, and under 0 ℃, add the 65mg sodium methylate, then, the gained mixture was in 0-10 ℃ of reaction 1 hour.Then, add 300mg 2-(2,4 difluorobenzene amino)-5-fluoro-6-(2,4,6-Three methyl Benzene sulfonyloxy) nicotinoyl) ethyl acetate and 115mg diacetyl oxide.The gained mixture reacted under room temperature 2 hours, and added 0.31ml2N hydrochloric acid and 3ml ethanol, and then, the gained mixture reacted under room temperature 1.5 hours.This reaction mixture is added in the mixture of 6ml methylene dichloride and 6ml water, tell organic layer, with the washing of 6ml saturated sodium-chloride water solution, anhydrous magnesium sulfate drying.Underpressure distillation removes and desolvates, and in the gained crystallisate, add the 2ml diisopropyl ether, then, filter and collect crystallization, obtain 245mg(productive rate 80.2%) 1-(2, the 4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-7-(2,4,6-Three methyl Benzene sulfonyloxy)-1,8-naphthyridine-3-carboxylic acid, ethyl ester.The physical properties of this compound is identical with example 41 gained compounds.

Example 47

200mg2-(6-(3-amino-1-the pyrrolidyl)-2-(2 that in 4ml toluene, suspends, 4-two fluoroanilino)-5-fluorine nicotinoyl) ethyl acetate, and add 170mgN, and N-methylformamide dimethyl acetal, then, the gained mixture is in the reaction down 7 hours that refluxes.Then, underpressure distillation removes and desolvates, and in the gained resistates, add the 1ml ether, then, filter and collect crystallization, obtain 195mg(productive rate 84.5%) 1-(2, the 4-difluorophenyl)-and 7-(3-(N, N-dimethylamino methylene imino-)-the 1-pyrrolidyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester, m.p.136-138 ℃.In the ethanol behind the recrystallization, m.p.:137-139 ℃.

IR（KBr）cm ^-1：ν _C＝o ^1730，1690

NMR(CDCl ₃) the δ value:

1.38（3H，t，J＝7Hz），1.65-2.15（2H，m），

2.85（6H，s），3.10-3.95（5H，m），

4.34（2H，q，J＝7Hz），6.75-7.70（4H，m），

7.92（1H，d，J＝13Hz），8.30（1H，s）

Example 48

In 4ml toluene, add 245mg(N, dinethylformamide-methyl-sulfate) coordination compound, and under the ice bath cooling, add the 66mg sodium methylate, then, the gained mixture reacted under room temperature 30 minutes.Then, add 200mg2-(6-(3-acetylaminohydroxyphenylarsonic acid 1-pyrrolidyl)-2-(2,4-two fluoroanilino)-5-fluorine nicotinoyl) ethyl acetate, the gained mixture is in the reaction down 5 hours that refluxes.In this reaction mixture, add 20ml chloroform and 20ml water, tell organic layer, with the washing of 20ml saturated sodium-chloride water solution, and with anhydrous magnesium sulfate drying.Underpressure distillation removes and desolvates; the gained resistates is with column chromatography (WaKo silica gel C-200; eluent: chloroform-ethanol (volume ratio 50: 1)) purify; obtain 190mg(productive rate 84.9%) 2-(6-(3-acetylaminohydroxyphenylarsonic acid 1-pyrrolidyl)-2-(2; 4-two fluoroanilino)-5-fluorine nicotinoyl)-3-(N; the N-dimethylamino) ethyl propenoate, m.p.184-186 ℃

IR（KB _r）cm ^-1：ν _C＝o ^{1680,1635（sh）}

NMR(CDCl ₃) the δ value:

2.91（6H，s），3.25-4.70（7H，m），6.45-7.10

（2H，m），7.38（1H，d，J＝14Hz），7.53（1H，s），

8.10-8.65（1H，m），11.62（1H，bs）

Example 49

In the 1ml dioxane, dissolve 80mg2-(2-(2,4-two fluoroanilino)-5-fluoro-6-hydroxyl nicotinoyl) ethyl acetate, 46mg diacetyl oxide and 50mg ethyl orthoformate, gained solution is in the reaction down 7 hours that refluxes, and then, underpressure distillation removes and desolvates.The gained resistates being dissolved in 10ml methyl alcohol and the 5ml water, and with 10%(weight) aqueous sodium carbonate is adjusted to pH8.5.The gained mixture reacted under room temperature 30 minutes, and with 2N hydrochloric acid reaction mixture was adjusted to pH2.0, then, added 20ml ethyl acetate and 10ml water.Tell organic layer, successively with 15ml water and the washing of 15ml saturated sodium-chloride water solution, and with anhydrous magnesium sulfate drying.Underpressure distillation removes and desolvates, and adds the 1ml ether in the gained resistates, then, filters and collects crystallization, obtains 43mg(productive rate 52.3%) 1-(2, the 4-difluorophenyl)-6-fluoro-1,4-dihydro-7-hydroxyl-4-oxo-1.8-naphthyridine-3-carboxylic acid, ethyl ester.The physical properties of this compound is identical with example 40 gained compounds.

Example 50

In the 1ml dioxane, dissolve 100mg2-(2-(2,4-two fluoroanilino)-5-fluoro-6-methoxyl group nicotinoyl) ethyl acetate, 55mg diacetyl oxide and 60mg ethyl orthoformate, gained solution is in the reaction down 7 hours that refluxes.Then, this reaction mixture is added in the mixture of 3ml ethyl acetate and 3ml water, tells organic layer, successively with 3ml water and the washing of 3ml saturated sodium-chloride water solution, and with anhydrous magnesium sulfate drying.Underpressure distillation removes and desolvates, and adds the 1ml ether in the gained crystallisate, then, filters and collects crystallization, obtains 45mg(productive rate 43.8%) 1-(2, the 4-difluorophenyl)-6-fluoro-1,4-dihydro-7-methoxyl group-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester.The physical properties of this compound is identical with example 41 gained compounds.

Example 51

(1) in ice bath cooling down at 4ml N, drip the 250mg phosphoryl chloride in the dinethylformamide, and add 200mg 2-(2-(2,4-two fluoroanilino)-5-fluoro-6-methoxyl group nicotinoyl) ethyl acetate, then, under same temperature, stirred 10 minutes.The gained mixture was in 50-60 ℃ of reaction 3.5 hours.This reaction mixture is poured in the 50ml frozen water, and adds the 20ml chloroform, then, tell organic layer, with 20ml water washing, anhydrous magnesium sulfate drying.Underpressure distillation removes and desolvates, and adds the 5ml ether in the gained resistates, then, filter and collect crystallization, obtain 150mg(productive rate 72.2%) 7-chloro-6-fluoro-1-(2, the 4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester, mp.217-220 ℃.With m.p. behind acetone-methyl alcohol (volume ratio 1: 1) recrystallization is 219-221 ℃.

Ultimate analysis C ₁₇H ₁₀N ₂O ₃ClF ₃

Calculated value (%): C, 53.35; H, 2.63; N, 7.32

Measured value (%): C, 53.61; H, 2.47; N, 6.96

(2) repeat the method for above-mentioned (1), starting compound is as shown in table 10, obtains the listed motif compound of table 10.

The physical properties of the listed motif compound of table 10 is identical with top (1) gained compound.

(3) repeat above the method for (1), by 2-(2-(4-fluoroanilino)-5-fluoro-6-hydroxyl nicotinoyl) ethyl acetate obtains 7-chloro-1-(4-fluorophenyl)-6-chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester, productive rate 74.9%.

M.p.:230-232 ℃ (acetone recrystallization)

IR（KBr）cm ^-1：ν _C＝0 ^1730，1700

NMR(CDCl ₃) the δ value:

1.38（3H，t，J＝7Hz），4.34（2H，q，J＝7Hz），

6.90-7.60（4H，m），8.37（1H，d，J＝7Hz），

8.53（1H，s）

Ultimate analysis C ₁₇H ₁₁N ₂O ₃ClF ₂

Calculated value (%): C, 55.98; H, 3.04; N, 7.68

Measured value (%): C, 56.09; H, 2.92; N, 7.68

(4) repeat the method for top (1), but replace phosphoryl chloride, obtain the listed result of table 11 with listedization of table 11 thing.

Table 11

Halogenide gained motif compound amount

(add-on) (productive rate)

Trichloromethylchloroformate 150mg

（160mg） （72.2%）

Phosphorus pentachloride 145mg

（340mg） （69.8%）

Phosphorus trichloride 125mg

（225mg） （60.1%）

The physical properties of each situation gained motif compound is identical with top (1) gained compound.

Example 52

(1) at 2ml 1, dissolving 130mg N in the 2-ethylene dichloride, dinethylformamide, and under the ice bath cooling, be added dropwise to the 270mg phosphoryl chloride, then, the gained mixture reacted 10 minutes under same temperature.Then, with 200mg 2-(2-(2,4-two fluoroanilino)-5-fluoro-6-methoxyl group nicotinoyl) ethyl acetate adds this reaction mixture, and the gained mixture is in the reaction down 4.5 hours that refluxes.In this reaction mixture impouring 30ml water, and add the 30ml chloroform.Tell organic layer, successively with 20ml water and the washing of 20ml saturated sodium-chloride water solution, and with anhydrous magnesium sulfate drying.Underpressure distillation removes and desolvates, the gained resistates is with column chromatography (WaKo silica gel C-200, eluent: benzene-ethyl acetate (volume ratio 10: 1)) purify, obtain 130mg(productive rate 62.6%) 7-chloro-1(2, the 4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester.The physical properties of this compound is identical with example 51 gained compounds.

(2) repeat top (1) same method, but replace N, dinethylformamide with 160ml N-carbonyl pyrrolidine; obtain 135mg(productive rate 65.0%) 7-chloro-1-(2; the 4-difluorophenyl)-and 6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester.The physical properties of this compound and example 51(1) the gained compound is identical.

Example 53

Suspension 200mg 2-in 4ml ethanol (6-(3-acetylaminohydroxyphenylarsonic acid 1-pyrrolidyl)-2-(2; 4-two fluoroanilino)-5-fluorine nicotinoyl)-3-(N, the N-dimethylamino) ethyl propenoate, and add 0.4ml 1N hydrochloric acid; then, the gained mixture reacted under room temperature 5 minutes.Then, in this reaction mixture, add 10ml chloroform and 10ml water, tell organic layer, successively with 10ml water and the washing of 10ml saturated sodium-chloride water solution, and with anhydrous magnesium sulfate drying.Underpressure distillation removes and desolvates, and adds the 4ml ether in the gained crystallisate, then, filter and collect crystallization, obtain 180mg(productive rate 98.6%) 7-(3-acetylaminohydroxyphenylarsonic acid 1-pyrrolidyl)-1-(2, the 4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester.The physical properties of this compound is identical with example 39 gained compounds.

Example 54

Suspension 200mg 2-in 4ml ethanol (6-(3-acetylaminohydroxyphenylarsonic acid 1-pyrrolidyl)-2-(2; 4-two fluoroanilino)-5-fluorine nicotinoyl)-3-(N, the N-dimethylamino) ethyl propenoate, and add 4ml 6N hydrochloric acid; then, the gained mixture is in the reaction down 3.5 hours that refluxes.Then, underpressure distillation removes and desolvates, and in the gained crystallisate, add 2ml ethanol, then, filter and collect crystallization, obtain 145mg(productive rate 85.4%) 7-(3-amino-1-pyrrolidyl)-1-(2, the 4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride.

M.p.:247-250 ℃ (decomposition) (concentrated hydrochloric acid-ethanol (volume ratio 1: 3) recrystallization)

IR（KBr）cm ^-1：ν _C＝o ¹⁷³⁰

NMR(TFA-d ₁) the δ value:

2.23-2.95（2H，m），3.38-4.83（5H，m），

6.95-7.90（3H，m），8.22（1H，d，J＝11Hz），

9.18（1H，s）

Example 55

In 20mlN, dissolving 1.00g 1-(2 in the dinethylformamide, the 4-difluorophenyl)-6-fluoro-1,4-dihydro-7-hydroxyl-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester, and under room temperature, add 570mg salt of wormwood and 520mg methyl-sulfate, then, the gained mixture reacted 4 hours under same temperature.In this reaction mixture, add 50ml water and 50ml ethyl acetate, tell organic layer, successively with 100ml water and the washing of 20ml saturated sodium-chloride water solution, and with anhydrous magnesium sulfate drying.Underpressure distillation removes and desolvates, and adds the 5ml ether in the gained crystallisate, then, filters and collects crystallization, obtains 950mg(productive rate 91.5%) 1-(2, the 4-difluorophenyl)-6-fluoro-1,4-dihydro-7-methoxyl group-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester.The physical properties of this compound is identical with example 41 gained compounds.

Example 56

Suspension 3.00g 1-(2 in the 30ml methylene dichloride, the 4-difluorophenyl)-6-fluoro-1,4-dihydro-7-hydroxyl-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester, and under the ice bath cooling, add 1.02g triethylamine and 2.20g neighbour-nitrobenzene sulfonyl chloride, then, the gained mixture reacted 30 minutes under same temperature and reacted 6 hours under room temperature.With this reaction mixture of water washing three times, use 50ml water at every turn, then, with anhydrous magnesium sulfate drying.Underpressure distillation removes and desolvates, and in the gained resistates, add the mixture of 6ml ethyl acetate and 12ml ether, then, filter the crystallization that collecting precipitation goes out, obtain 4.40g(productive rate 97.2%) 1-(2, the 4-difluorophenyl)-6-fluoro-1,4-dihydro-7-(2-oil of mirbane sulfonyloxy)-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester, m.p.157-160 ℃.

M.p.:162-163 ℃ (acetone-normal hexane (volume ratio 10: 1) recrystallization)

IR（KBr）cm ^-1：ν _C＝o ^{1730，1700（sh）}

NMR(DMSO-d ₆) the δ value:

1.30（3H，t，J＝7Hz），4.24（2H，q，J＝7Hz），

7.03-8.26（7H，m），8.64（1H，d，J＝9Hz），

8.72（1H，s）

With above-mentioned same method, obtain the listed compound of table 12.

Example 57

Suspension 500mg 1-(2 in the 5ml anhydrous acetonitrile, the 4-difluorophenyl)-6-fluoro-1,4-dihydro-7-hydroxyl-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester, and under the ice bath cooling, add 150mg triethylamine and 410mg diphenyl phosphoryl chloride, then, the gained mixture reacted under room temperature 2 hours.In this reaction mixture, add 25ml methylene dichloride and 25ml water, tell organic layer, wash twice successively with water, each 20ml, and with the washing of 20ml saturated sodium-chloride water solution, then, with anhydrous magnesium sulfate drying.Underpressure distillation removes and desolvates, and in the gained resistates, add the 15ml ether, then, filter the crystallization that collecting precipitation goes out, obtain 700mg(productive rate 85.5%) 1-(2, the 4-difluorophenyl)-7-(two phenoxy group phosphonatos)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester, m.p.144-147 ℃.The physical properties of this compound is the same with example 44 gained compounds.

With top same method, obtain 7-(diethoxy phosphonium mesitoyl oxygen base)-1-(2, the 4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester, the physical properties of this compound is the same with example 44 gained compounds.

Example 58

The 500mg1-(2 that in the 5ml pyridine, suspends, the 4-difluorophenyl)-6-fluoro-1,4-dihydro-7-hydroxyl-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester, and add 770mg diphenylphosphine acylazide, then, the gained mixture was in 80 ℃ of reactions 4 hours.Underpressure distillation removes and desolvates, and adds 10ml ethyl acetate and 10ml water in the gained resistates, then, with 6N hydrochloric acid the gained mixture is adjusted to pH2.0.Tell organic layer, use 5ml saturated sodium bicarbonate aqueous solution and 5ml water washing successively, anhydrous magnesium sulfate drying.Underpressure distillation removes and desolvates, in the gained resistates, add the 5ml ether, filter the crystallization that collecting precipitation goes out then, obtain 440mg(productive rate 82.3%) 7-azido--1-(2, the 4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester, m.p.176-177.5 ℃.The physical properties of this compound is the same with example 44 gained compounds.

Example 59

In the 10ml methylene dichloride, dissolve 1.00g1-(2, the 4-difluorophenyl)-7-ethylmercapto group-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester, and between adding 580mg-(purity: 80%), then, the gained mixture reacted 5 hours down in the ice bath cooling chlorine peroxybenzoic acid.The filtering precipitation adds 10ml water in gained filtrate, then, be adjusted to pH7.5 with saturated sodium bicarbonate aqueous solution.Tell organic layer, with the 10ml water washing, with anhydrous magnesium sulfate drying.Underpressure distillation removes and desolvates; with column chromatography (WaKo silica gel C-200; eluent: toluene-ethyl acetate (volume ratio is 10: 1) is purified; obtain 810mg(productive rate 77.9%) 1-(2; the 4-difluorophenyl)-7-second sulfinyl-6-fluoro-1; 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester, m.p.150-151 ℃.The physical properties of this compound is the same with example 44 gained compounds.

With top same method, obtain 7-benzenesulfinyl-1-(2, the 4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester.The physical properties of this compound is the same with example 44 gained compounds.

Example 60

Dissolving 1.00g 1-(2 in the 15ml methylene dichloride, the 4-difluorophenyl)-7-ethylmercapto group-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester, and between adding 1.06g-chlorine peroxybenzoic acid (purity: 80%), then, the gained mixture reacted 30 minutes under the ice bath cooling, and reaction is 4 hours under the room temperature.Remove by filter precipitation, in gained filtrate, add 10ml water, then, be adjusted to pH7.5 with saturated sodium bicarbonate aqueous solution.Tell organic layer, successively with 10ml water and the washing of 10ml saturated sodium-chloride water solution, and with anhydrous magnesium sulfate drying.Underpressure distillation removes and desolvates, and adds the 10ml ether in the gained resistates, then; filter the crystallization that collecting precipitation goes out, obtain 940mg(productive rate 87.2%) 1-(2,4-difluorophenyl-7-ethylsulfonyl-6-fluoro-1; 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester, m.p.215-217 ℃.The physical properties of this compound is the same with example 44 gained compounds.

With top same method, obtain 7-benzenesulfonyl-1-(2, the 4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester, the physical properties of this compound is the same with example 44 gained compounds.

Example 61

Suspension 800mg 7-benzenesulfonyl-1-(2 in the 8.0ml dioxane, the 4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1; 8-naphthyridine-3-carboxylic acid, ethyl ester; and add 4.9ml 1N hydrochloric acid, then, the gained mixture is in the reaction down 4 hours that refluxes.Underpressure distillation removes and desolvates; the gained resistates is through column chromatography (WaKo silica gel C-200; eluent: benzene-ethyl acetate (volume ratio 10: 1) is purified; obtain 560mg(productive rate 74.3%) 7-benzenesulfonyl-1-(2; the 4-difluorophenyl)-6-fluoro-1; 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, m.p.252-258 ℃.

M.p.:259-263 ℃ (dioxane recrystallization)

IR（KBr）cm ^-1：ν _C＝O ¹⁷³⁰

NMR(DMSO-d ₆) the δ value:

7.05-7.85（8H，m），8.85（1H，d，J＝9Hz），

8.98（1H，s）

Example 62

Suspension 500mg 1-(2 in the 2.5ml phosphoryl chloride, the 4-difluorophenyl)-and 6-fluoro-1,4-dihydro-7-methoxyl group-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester, gained suspension is in the reaction down 1.5 hours that refluxes, underpressure distillation removes and desolvates, and the gained crystallisate obtains 430mg(productive rate 85.0% with the washing of 10ml ether) 7-chloro-1-(2, the 4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester, m.p.216-219 ℃.The physical properties of this compound is the same with example 51 gained compounds.

Example 63

Suspension 500mg 7-chloro-1-(2 in the 10ml concentrated hydrochloric acid, the 4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester, gained suspension is in the reaction down 1 hour that refluxes.Reaction mixture is with the dilution of 10ml water, and the crystallization that filtering-depositing goes out with the 2ml water washing, obtains 450mg(productive rate 97.1%) 7-chloro-1-(2, the 4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, m.p.238-242 ℃.

M.p.:242-243.5 ℃ (chloroform-ethanol (volume ratio 2: 1) recrystallization)

Example 64

Suspension 150mg 3-amino-pyrrolidine dihydrochloride in 5ml ethanol, and adding 310mg triethylamine obtains a kind of solution.Then, add 500mg 1-(2, the 4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-7-(2,4,6-tri isopropyl benzenesulfonyl oxygen base)-1,8-naphthyridine-3-carboxylic acid, ethyl ester, gained mixture reacted under room temperature 2 hours.Then, in this reaction mixture, add 6ml water, filter out the crystallization that is settled out, with the 5ml water washing, obtain 330mg(productive rate 96.3%) 7-(3-amino-1-pyrrolidyl)-1-(2, the 4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester, m.p.200-202 ℃.

M.p.:206-209 ℃ (ethyl acetate-ethanol (volume ratio 1: 1) recrystallization)

NMR(TFA-d ₁) the δ value:

1.48（3H，t，J＝7Hz），2.19-2.86（2H，m），

3.33-4.90（7H，m），6.89-7.85（3H，m），

8.18（1H，d ₁J＝11Hz），9.04（1H，s）

With above-mentioned identical method, obtain the listed compound of table 13.

Example 65

270 milligrams of Piperazine anhydrous are dissolved in 4 milliliters of methylene dichloride, in this solution, add 400 milligrams of 1-(2, the 4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-7(2,4,6-tri isopropyl benzenesulfonyl oxygen base)-1,8-naphthyridine-3-carboxylic acid, ethyl ester is put in the ice bath reaction 1 hour with this mixed solution.In this mixed solution, add 20 milliliters of ethyl acetate and 10 ml waters.Separate organic layer, successively with 10 milliliters of saturated sodium bicarbonate aqueous solutions and 10 milliliters of saturated sodium-chloride water solution washings.Use anhydrous magnesium sulfate drying.Underpressure distillation removes and desolvates.In the crystallization that obtains, add 5 milliliters of ether, filter, obtain 1-(2, the 4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-250 milligrams of (productive rates: 91.2%) of 3-carboxylic acid, ethyl ester crystallization.Fusing point: 208-211 ℃.

Fusing point: 220-223 ℃ (recrystallization in acetone-methyl alcohol (1: 1 volume))

NMR(TFA-d ₁) the δ value:

1.50（3H，t，J＝7Hz），3.39-3.93（4H，m），

3.93-4.44（4H，m），4.66（2H，q，J＝7Hz），

6.89-7.82（3H，m），8.32（1H，d，J＝12Hz），

9.14（1H，s）

With above-mentioned identical method, the product of gained is listed in table 14:

Table 14

The physical properties productive rate of starting compound resultant

X R ²（%）

H

Fusing point: 215-217 ℃ 90.1

NMR（TFA-d ₁）δvalues：

1.51（3H，t，J＝7Hz），

3.40-3.88（4H，m），4.06-

4.46（4H，m），4.70（2H，

q，J＝7Hz），7.16-7.78

（4H，m），8.38（1H，d，

J＝12Hz），9.21（1H，s）

H

The same 91.1

F MeSO ₃-with example 65 gained compound physical properties identical 64.7

F

The same 70.6

F F ₃CSO ₃-the same 63.1

Example 66

(1) 64 milligram of 3-amino-pyrrolidine dihydrochloride is suspended in 2 milliliters of ethanol, adds 130 milligrams of triethylamines in this suspension.Then, in this solution, add 200 milligrams of 1-(2,4-difluorophenyl)-7-hexichol oxygen phosphorus acyloxy-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester.This mixture was in room temperature reaction 1 hour.Then, add 3 ml waters, the crystallization that collecting precipitation goes out.With 3 ml water wash crystallizations, obtain 7-(3-amino-1-pyrrolidyl)-1-(2, the 4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,110 milligrams of (productive rates: 75.9%) of the crystallization of 8-naphthyridine-3-carboxylic acid, ethyl ester.The physical properties of this compound is identical with example 64 gained compounds.

(2) remove with 170 milligrams of 7-diethoxy phosphoryl oxy-1-(2, the 4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester replaces 1-(2, the 4-difluorophenyl)-7-two phenoxy group phosphorus acyloxy-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester, other operation steps is with (1).Obtain 7-(3-amino-1-pyrrolidyl)-1-(2, the 4-difluorophenyl)-6-fluoro-1, the mix physical properties of 105 milligrams of (productive rate 71.5%) these compounds of crystallization of naphthalene-3-carboxylic acid, ethyl ester of 4-dihydro-4-oxo-1,8-dichloro is identical with example 64 gained compounds.

Example 67

4.5 milliliter ethanol and 4.5 milliliters of N, after dinethylformamide mixes, add 400 milligrams of Piperazine anhydrous, in this solution, add 450 milligrams of 7-azido--1-(2, the 4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester, this mixed solution was 80 ℃ of reactions 1 hour.Underpressure distillation removes and desolvates.In the gained residue, add 30 milliliters of ethyl acetate and 30 ml waters.Then pH value of solution is transferred to 1.0 with 2N hydrochloric acid.Separate water layer, in water layer, add 15 milliliters of chloroforms.With the 1N aqueous sodium hydroxide solution this pH value of solution is transferred to 8.5 again.Separate organic layer, with 10 ml waters and 10 milliliters of saturated sodium-chloride water solution washings, use anhydrous magnesium sulfate drying successively.Underpressure distillation removes and desolvates, and adds 5 milliliters of ether in the gained residue, filters out sedimentary crystallization, obtain 1-(2, the 4-difluorophenyl)-and 6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,420 milligrams of (productive rates: 84.0%) of the crystallization of 8-naphthyridine-3-carboxylic acid, ethyl ester.The physical properties of this compound is identical with example 65 gained compounds.

Example 68

With 400 milligrams of 1-(2, the 4-difluorophenyl)-and 6-fluoro-1,4-dihydro-4-oxo-7-thiophenyl-1,8-naphthyridine-3-carboxylic acid, ethyl ester and 380 milligrams of Piperazine anhydrous are suspended in 12 milliliters of N, among the dinethylformamide, this suspension was in 95-100 ℃ of reaction 6 hours.Then, underpressure distillation removes and desolvates.In residue, add 10 milliliters of ethyl acetate and 30 ml waters, then this pH value of solution is transferred to 0.5 with 6N hydrochloric acid.Separating water layer, add 30 milliliters of ethyl acetate, use 10%(weight again) wet chemical transfers to 9.0 with this pH value of solution.Separate organic layer, with 2 20 milliliters of ethyl acetate extraction water layers.Extraction liquid and organic layer merge.Amalgamation liquid washs with 20 milliliters of saturated nacl aqueous solutions, uses anhydrous magnesium sulfate drying.Underpressure distillation removes and desolvates.In the gained crystallization, add 5 milliliters of ether, filter, obtain 1-(2, the 4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-7(1-piperazinyl)-1,230 milligrams of (productive rates: 60.7%) of the crystallization of 8-naphthyridine-3-carboxylic acid, ethyl ester.The physical properties of this compound is identical with the compound of example 65 gained.

Example 69

(1) 120 milligram of 3-amino-pyrrolidine dihydrochloride is suspended in 3 milliliters of acetate; add 250 milligrams of triethylamines, and then add 300 milligrams of 7-benzenesulfinyl-1-(2,4-difluorophenyl)-6-fluoro-1; 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester.This mixed solution was room temperature reaction 3 hours, then add 10 milliliters of ether, filter out crystallization, with 12 ml water wash crystallizations, obtain 7-(3-amino-1-pyrrolidyl)-1-(2, the 4-difluorophenyl)-and 6-fluoro-1,4-dihydro-4-oxo-1,230 milligrams of the crystallizations of 8-naphthyridine-3-carboxylic acid, ethyl ester (productive rate 83.8%).The physical properties of this compound is identical with example 64 gained compounds.

(2) remove with 270 milligrams of 1-(2; the 4-difluorophenyl)-7-second sulfinyl-6-fluoro-1; 4-dihydro-4-oxo-1; 8-naphthyridine-3-carboxylic acid, ethyl ester replaces 7-benzenesulfinyl-1-(2; the 4-difluorophenyl)-6-fluoro-1; 4-dihydro-4-oxo-1; outside 8-naphthyridine-3-carboxylic acid, ethyl ester; other operation steps is with (1); obtain 7-(3-amino-1-pyrrolidyl)-1-(2; the 4-difluorophenyl)-and 6-fluoro-1,4-dihydro-4-oxo-1,230 milligrams of (productive rates: 83.6%) of the crystallization of 8-naphthyridine-3-carboxylic acid, ethyl ester.The physical properties of this compound is identical with the compound of example 64 gained.

Example 70

(1) 120 milligram of 3-amino-pyrrolidine dihydrochloride is suspended in 3 milliliters of ethanol; add 250 milligrams of triethylamines; and then add 300 milligrams of 7-benzenesulfonyl-1-(2; the 4-difluorophenyl)-6-fluoro-1; 4-dihydro-4-oxo-1; 8-naphthyridine-3-carboxylic acid, ethyl ester, the gained mixed solution was 45～50 ℃ of reactions 4 hours.In this reaction mixture, add 10 milliliters of ether, filter, with 12 ml water wash crystallizations, obtain 7-(3-amino-1-pyrrolidyl)-1-(2, the 4-difluorophenyl)-and 6-fluoro-1,4-dihydro-4-oxo-1,230 milligrams of (productive rates: 86.6%) of the crystallization of 8-naphthyridine-3-carboxylic acid, ethyl ester.The physical properties of this compound is identical with example 64 gained compounds.

(2) remove with 270 milligrams of 1-(2; the 4-difluorophenyl)-7-ethylsulfonyl-6-fluoro-1; 4-dihydro-4-oxo-1; 8-naphthyridine-3-carboxylic acid, ethyl ester replaces 7-benzenesulfonyl-1-(2; the 4-difluorophenyl)-6-fluoro-1; 4-dihydro-4-oxo-1; outside 8-naphthyridine-3-carboxylic acid, ethyl ester; other operation steps is with (1); obtain 7-(3-amino-1-pyrrolidyl)-1-(2; the 4-difluorophenyl)-and 6-fluoro-1,4-dihydro-4-oxo-1,225 milligrams of (productive rates: 84.9%) of the crystallization of 8-naphthyridine-3-carboxylic acid, ethyl ester.The physical properties of this compound is identical with example 64 gained compounds.

Example 71

70 milligrams of N-ethanoyl piperazine mono-hydrochloric salts are suspended in 2 milliliters of methylene dichloride; add 80 milligrams of triethylamines; and then add 200 milligrams of 1-(2; the 4-difluorophenyl)-6-fluoro-1; 4-dihydro-4-oxo-7-(2,4,6-tri isopropyl benzenesulfonyl oxygen base)-1; 8-naphthyridine-3-carboxylic acid, ethyl ester, this mixed solution was in room temperature reaction 2 hours.In this reaction mixture, add 8 milliliters of methylene dichloride and 10 ml waters, separate organic layer, use anhydrous magnesium sulfate drying successively with 10 ml waters and 10 milliliters of saturated sodium-chloride water solution washings.Underpressure distillation removes and desolvates; in the gained residue, add 5 milliliters of ether; filter; obtain 7-(4-ethanoyl-1-piperazinyl)-1-(2; the 4-difluorophenyl)-6-fluoro-1; 4-dihydro-4-oxo-1, and 140 milligrams of the crystallizations of 8-naphthyridine-3-carboxylic acid, ethyl ester (productive rate: 93.1%), fusing point: 217-219 ℃.The physical properties of this compound is identical with the compound of example 39 gained.

Example 72

1.00 gram 7-(3-amino-1-pyrrolidyl)-and 1-(2, the 4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester are suspended in 6 milliliters of 6N hydrochloric acid, this suspension returning reaction 2 hours.Then, add 6 ml waters, filter with 2 ml water wash crystallizations, obtain 7-(3-amino-1-pyrrolidyl)-1-(2, the 4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1, and 920 milligrams of the crystallizations of 8-naphthyridine-3-carboxylic acid hydrochloride (productive rate: 90.2%), fusing point: 247-250 ℃ (decomposition).The physical properties of this compound is identical with the compound of example 54 gained.

With above-mentioned identical method, can obtain: 7-(3-amino-1-pyrrolidyl)-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride.

Fusing point: 210-217 ℃ (decomposition)

NMR(TFA-d ₁) the δ value:

2.20-2.85（2H，m），3.48-4.98（5H，m），

7.07-7.78（4H，m），8.18（1H，d，J＝11Hz），

9.18（1H，s）

Example 73

200 milligrams of 1-(2, the 4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid, ethyl ester is suspended in 1.2 milliliters of 6N hydrochloric acid, this suspension returning reaction 2 hours.Then, add 2 ml waters, filter, with 1 ml water wash crystallization, obtain 1-(2, the 4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1, and 190 milligrams of the crystallizations of 8-naphthyridine-3-carboxylic acid hydrochloride (productive rate: 93.2%), fusing point: 249-252 ℃ (decomposition)

Fusing point: 249-252 ℃ (decomposition) ((recrystallization in concentrated hydrochloric acid-methyl alcohol (1: 2 volume)).

NMR(TFA-d ₁) the δ value:

3.33-3.92（4H，m），3.92-4.50（4H，m），

6.90-7.90（3H，m），8.30（1H，d，J＝12Hz），

9.18（1H，s）

Example 74

100 milligrams of 1-(2, the 4-difluorophenyl)-7-(3-(N, N-dimethylamino methylene imino-)-1-pyrrolidyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester are suspended in 1 milliliter of 6N hydrochloric acid, this suspension returning reaction 2 hours.Then, underpressure distillation removes and desolvates, and adds 1 milliliter of ethanol in the gained crystallisate, filter, obtain 7-(3-amino-1-pyrrolidyl)-1-(2, the 4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,85 milligrams of (productive rates: 94.0%) of the crystallization of 8-naphthyridine-3-carboxylic acid hydrochloride.The physical properties of this compound is identical with the compound of example 54 gained.

Example 75

500 milligrams of 7-(3-acetylaminohydroxyphenylarsonic acid 1-pyrrolidyls)-1-(2, the 4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester is dissolved in 5 milliliters of 6N hydrochloric acid, gained solution back flow reaction 4 hours, then, filter, with 1 ml water wash crystallization, obtain 7-(3-amino-1-pyrrolidyl)-1-(2, the 4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,390 milligrams of the crystallizations of 8-naphthyridine-3-carboxylic acid hydrochloride (productive rate: 84.0%), fusing point: 247-250 ℃ (decomposition).The physical properties of this compound is identical with example 54 gained compounds.

Example 76

Except that the reaction times made into 2 hours, other operation steps obtains 1-(2 with example 75, the 4-difluorophenyl)-6-fluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride (productive rate: 91.5%).The physical properties of this compound is identical with example 73 gained compounds.

Claims (9)

1, the preparation general formula following 1, the method for 4-dihydro-4-oxo-naphthyridines derivatives or its salt,

R in the formula ¹Represent hydrogen or carboxyl-protecting group, R ²Represent halogen, hydroxyl, azido-maybe can be substituted with 1,2 or 3 C _1-4The C of alkyl, halogen atom or nitro _1-4Alkoxyl group, C _1-4Alkylthio, thiophenyl, C _1-4Alkyl sulfinyl, benzenesulfinyl, C _1-4Alkane alkylsulfonyl, benzenesulfonyl, C _1-4Alkane sulfonyloxy, phenylsulfonyloxy, naphthalene sulfonyl oxygen base, two-C _1-4Alcoxyl phosphorus acyloxy or hexichol oxygen phosphorus acyloxy, perhaps 3-amino-1-pyrrolidyl (wherein amino can be protected) or 1-piperazinyl (wherein imino-can be protected); X represents hydrogen or fluorine,

The feature of this method is the following 2-of general formula (5-fluorine nicotinoyl) acetogenin or its salt:

R wherein ^1aThe representation carboxy protecting group, R ²Identical with X, following N with general formula with above-mentioned implication, the acetal of N-two substituted formamides is having or is not having reaction in the presence of the acid anhydrides,

R in the formula ³And R ⁴Can be identical also can be different, represent alkyl or cycloalkyl separately, also can connect together forms an alkylidene group, this alkylidene group with Form ring, R ⁵And R ⁶Can be identical also can be different; represent alkyl separately or form heterocycle with contiguous nitrogen; or there is being or do not having in the presence of the diacetyl oxide reaction with alkyl orthoformate; reaction solvent is selected from aromatic hydrocarbon, halohydrocarbon, ethers, ester class, ketone, nitrile, ethanol, acid amides, sulfoxide or pyridine; temperature of reaction is 0-150 ℃; if desired, can remove protecting group or converted product is its salt or ester.

2, according to the method for claim 1, the R in the starting compound ³, R ⁴, R ⁵And R ⁶Represent alkyl.

3, according to the method for claim 2, the R in the starting compound ³, R ⁴, R ⁵And R ⁶Represent methylidene.

4, the preparation general formula following 1, the method for 4-dihydro-4-oxo naphthyridines derivatives or its salt,

R ' represents hydrogen or carboxyl-protecting group in the formula, and X represents hydrogen or fluorine, and Y represents halogen atom, and the feature of this method is, the compound or its salt that general formula is following,

R wherein ^1aThe representation carboxy protecting group, R ^2bRepresentation hydroxy maybe can be substituted with 1-3 C _1-4The C of alkyl, halogen atom or nitro _1-4Alkoxyl group, C _1-4Alkane alkylsulfonyl, benzenesulfonyl, C _1-4Alkane sulfonyloxy, phenylsulfonyloxy, naphthalene sulfonyl oxygen base, two-C _1-4Alcoxyl phosphorus acyloxy or hexichol oxygen phosphorus acyloxy, X is identical with above-mentioned implication,

With by N, the Wei Ersi Mel reagent react that N-two substituted formamides produce, reaction solvent is selected from aromatic hydrocarbon, halohydrocarbon or methane amide, temperature of reaction is 0-150 ℃, if necessary, can remove carboxyl-protecting group or converted product is its salt or ester.

5, by the method for claim 4, wherein Wei Ersi Mel reagent is by the following N of general formula, N-two substituted formamides,

R in the formula ⁷And R ⁸Can be the same or different, represent alkyl or aryl separately or form a nitrogen heterocyclic ring with contiguous nitrogen-atoms, this heterocycle can contain sulphur or Sauerstoffatom except that nitrogen-atoms,

With the inorganic halides that is selected from phosphoryl halogen and halogenation sulphur or be selected from carbonyl halide, the Organohalogen compounds of oxalyl halogen and dibromo triphenyl phosphine reaction and getting.

6, according to the method for claim 5, the R in the starting compound ⁷And R ⁸Represent alkyl.

7, according to the method for claim 6, the R in the starting compound ⁷And R ⁸Represent methylidene.

8, according to the method for claim 4, the R in the starting compound ^2bRepresentation hydroxy or C _1-4Alkoxyl group.

9, according to claim 1 or 4 preparations 1, the method for 4-dihydro-4-oxo-naphthyridines derivatives or its salt, the R in the starting compound ²Or R ^2bRepresent 2,4 separately, 6-Three methyl Benzene sulfonyloxy or 2,4,6-tri isopropyl benzenesulfonyl oxygen base.