CN1062906A - The preparation method of 8-chloroquinolone derivatives - Google Patents

The preparation method of 8-chloroquinolone derivatives Download PDF

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CN1062906A
CN1062906A CN91110833A CN91110833A CN1062906A CN 1062906 A CN1062906 A CN 1062906A CN 91110833 A CN91110833 A CN 91110833A CN 91110833 A CN91110833 A CN 91110833A CN 1062906 A CN1062906 A CN 1062906A
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行本裕介
金内彻
木村阳一
川上胜浩
旱川勇夫
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Daiichi Pharmaceutical Co Ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

A kind of preparation is by the method for the 8-chloroquinolone derivatives of formula (II) representative, and this method comprises the quinolone compounds of (I) and chlorination reaction, X, R in the formula 1And R 2Such as in the specification sheets definition. X, R in the formula 1And R 2Definition with above-mentioned identical.

Description

The preparation method of 8-chloroquinolone derivatives
The invention relates to the method for preparing the 8-chloroquinolone derivatives, this compound has potential anti-microbial activity and high security, thereby is expected as a kind of synthetic antiseptic-germicide.
The 8-chloro-7-of formula II described below or (III) representative replaces-1-(2-fluorine cyclopropyl)-derivative of 4-quinolone can be used as effective antiseptic-germicide, and is flat as EP-A-0341493 and Jp-A-()-2-231475(" Jp-A " here is " unexamined disclosed Japanese patent application ").Disclosed such.
These compounds now can be from 3-chloro-2,4, and the 5-trifluoro-benzoic acid begins to prepare.As if but owing to will obtain highly purified 3-chloro-2,4, the 5-trifluoro-benzoic acid is difficulty quite, and is synthetic because its is difficult to, so do not have economic worth by this compound as this method of raw material.
The objective of the invention is to provide a kind of method of the simple and maneuverable 8-of preparation chloroquinolone derivatives, this method has high economic benefit.
According to further result of study, the inventor founded a kind of simple, easily, can obtain the preparation method of high yield and highly purified 8-chloroquinolone derivatives simultaneously again.
The prepared 8-chloroquinolone derivatives of method of the present invention is represented by logical formula II:
Figure 911108335_IMG9
X represents halogen atom in the formula; R 1Represent hydrogen atom, C 1-C 6The alkyl or phenyl alkyl, wherein phenyl moiety can have nitro, chlorine atom or alkoxyl group; And R 2Representative contains one or two nitrogen-atoms 4-8 unit saturated heterocyclyl as annular atoms, this heterocyclic radical also can contain Sauerstoffatom or sulphur atom as annular atoms, and one or more substituting groups that are selected from following this group group can be arranged: amino, single alkane or dialkylamino (its moieties has 1-6 carbon atom), C 2-C 7Alkyl-carbonyl-amino, C 2-C 7Alkoxycarbonyl amino, C 2-C 7Halogenated alkyl carbonyl, C 2-C 7Halo alkoxy carbonyl amino, phenyl alkoxycarbonyl amino (its phenyl moiety can have nitro or chlorine atom), C 1-C 6Alkyl, C 2-C 6Alkylidene group (it forms a volution with constituting carbon atom of heterocyclic), halogen atom and C 1-C 6Alkoxyl group, this method comprises the quinolone compounds and the chlorination reaction of formula I,
Figure 911108335_IMG10
X, R in the formula 1And R 2Definition with above identical.
The present invention also provides the method for a kind of preparation by the 8-chloroquinolone derivatives of formula III representative,
Figure 911108335_IMG11
X represents halogen atom in the formula; R 3Representative contains the saturated heterocyclyl of one or two nitrogen-atoms as the 4-8 of annular atoms, this heterocyclic radical also can contain oxygen or sulphur atom also can have one or more substituting groups as an annular atoms, and this substituting group is selected from: amino, an alkane or dialkylamino (its moieties has 1-6 carbon atom), C 1-C 6Alkyl, C 2-C 6Alkylidene group (it forms a volution with a carbon atom that constitutes heterocyclic radical), halogen atom, and C 1-C 6Alkoxyl group, this method comprises the hydrolysis of removing protecting group and/or ester group of formula II compound.
Made the result of further research, the inventor has successfully developed the method that a kind of chlorination by the formula I compound prepares the formula II compound.
Can be used for chlorizating agent of the present invention and comprise SULPHURYL CHLORIDE, clorox, N-chlorosuccinimide, chlorine and the hypochlorous acid ester of representing by formula IV:
R 4OCl（Ⅳ）
R in the formula 4Represent C 1-C 6Alkyl, benzene alkyl or chlorinated benzene alkyl.
In above these chlorizating agents, according to reason described below, the hypochlorous acid ester is preferred a kind of chlorizating agent.
Heterocyclic radical R 2On have the chlorization of amino formula I compound to be attended by to pay reaction, the result makes the purity drop of productive rate and product, unless amido protecting is got up.If use the amino formula I compound of protection, then need additional two step-introducing protecting groups and remove protecting group.But the introducing of protecting group and removing, except increasing step, each step all can produce disadvantageous pair of reaction, is directed at productive rate and purity further reduces.
In the process of easy synthetic route, use the hypochlorous acid ester of formula IV can solve above-mentioned such problem as chlorizating agent in the economy of studying the 8-chloroquinolone derivatives, this has been confessedly.In other words, make chlorizating agent with the hypochlorous acid ester of formula IV and can make heterocyclic radical R 2, the chlorization of the formula I compound that last band is amino produces high yield and highly purified chlorizate formula II compound no matter being improved and whether amino is protected.
The hypochlorous acid ester of formula IV comprises more hypochlorous alkyl esters, for example: propyl ester (as the n-propyl and the isopropyl ester of hypochlorous acid), butyl ester (as positive butyl ester, isobutyl ester, secondary butyl ester, the tert-butyl ester of hypochlorous acid) and benzyl ester serve as preferred with the hypochlorous acid tertiary butyl ester wherein.
These hypochlorous esters are to use the general method synthetic, promptly by mixture and the chlorine reaction of alcohol with hypochlorite reaction or pure and mild alkaline hydrated oxide (as sodium hydroxide).
Work as substituent R 2During further by amino a replacement, this amino can protect it with protecting group.Can be used to protection at R 2On the protecting group of amino comprise alkyl carbonyl, carbalkoxy, alkyl halide carbonyl, alkyl halide oxygen carbonyl, benzene carbalkoxy, and nitro or chlorinated benzene carbalkoxy.The specific example of protecting group is ethanoyl, chloracetyl, 2,2,2-trichloro-ethoxycarbonyl, to the nitro carbobenzoxy-(Cbz), and to the benzyloxycarbonylchloride base.
In formula I, (II) and (III), R 2Or R 3The heterocyclic radical of representative is one, and to be referred to as meaning ring from the cyclammonium deutero-amino.Cyclammonium is to remove to replace the carbon atom that constitutes this ring and a kind of compound of deutero-by alicyclic compound by a nitrogen-atoms.The amino R of preferred ring 2Be 4-7 unit ring, more preferably 5 or 6 yuan of rings also can further contain a Sauerstoffatom, sulphur atom and/or another nitrogen-atoms in its ring.The example oxazolidine of such ring amino, morpholine, thiazolidine, thiomorpholine, imidazolidine, pyrazolidine, piperazine, particularly preferably be tetramethyleneimine and piperazine.
As mentioned above, ring amino can contain one or several substituting group, for example polar group (as replacing or amino, the replacement that does not replace or the aminoalkyl that does not replace, 5-replace-2-oxygen-1,3-Er Evil is luxuriant-the 4-ylmethyl, and hydroxyl); And C 1-C 6Straight chain, side chain or cyclic alkyl.In these substituting groups, polar group can be connected with the alkyl chain that mostly is most 6 carbon atoms.The suitable substituting group of above-mentioned amino comprises alkyl, acyl group and carbalkoxy.Preferred polar group comprises unsubstituted amino, amino methyl, 1-amino-ethyl and hydroxyl.Preferably include methyl, ethyl, propyl group, gem-dimethyl and together with diethyl as the substituent alkyl of ring on the amino.Thereby this alkyl substituent also is preferably formed as the volution that a cyclopropane ring or tetramethylene ring generate an associative ring amino.In addition, 4-7 unit ring amino can encircle amino crosslinked with this and form bicyclic amino group.
These rings suitable example amino, the especially amino ring amino that replaces is expressed as follows:
Figure 911108335_IMG12
R wherein 5, R 6, R 7, R 8, R 9, R 10, R 11, R 12, R 13, R 14With 15Each all represents hydrogen atom or C 1-C 6Alkyl; R 14And R 15Can be connected to each other a methene chain of formation and obtain 3-6 unit ring, constitute a spirane structure therefrom.
The specific examples of the heterocyclic radical that these are nitrogenous is a 3-amino-pyrroles alkyl, 3-methylamino pyrrolidyl, 3-dimethylamino pyrrolidyl, 3-ethylamino pyrrolidyl, 3-propyl group amino-pyrroles alkyl, 3-sec.-propyl amino-pyrroles alkyl, 3-amino-4-methylpyrrole alkyl, 4-amino-2-methyl pyrrolidyl, 4-amino-2, the 3-alkyl dimethyl pyrrole, 3-methylamino-4-methylpyrrole alkyl, 4-methylamino-2-methylpyrrole alkyl, 4-methylamino-2, the 3-alkyl dimethyl pyrrole, 3-dimethylamino-4-methylpyrrole alkyl, 4-dimethylamino-2-methylpyrrole alkyl, 4-dimethylamino-2, the 3-alkyl dimethyl pyrrole, 3-methylpiperazine base, 4-methylpiperazine base, 3,4-lupetazin base, 3,5-lupetazin base, 3,4,5-tri methyl piperazine base, 4-ethyl-3,5-lupetazin base, 4-sec.-propyl-3,5-lupetazin base, 3-aminomethyl pyrrolidine base, 3-methylamino methylpyrrole alkyl, 3-(1-amino) N-ethyl pyrrole N-alkyl, the 3-(1-methylamino) N-ethyl pyrrole N-alkyl, the 3-(1-ethylamino) N-ethyl pyrrole N-alkyl, 3-(1-amino) propyl pyrrole alkyl, the 3-(1-methylamino) propyl pyrrole alkyl, 3-amino-pyrroles alkyl, 4-amino-3, the 3-alkyl dimethyl pyrrole, 7-amino-5-azaspiro [2,4] heptane-5-base, 8-amino-6-azaspiro [3,4] octane-6-base, 1,4-2 azabicyclo [3,2,1] octane-4-base, 3,8-diazabicyclo [3,2,1] octane-3-base, 8-methyl-3,8-diazabicyclo [3,2,1]-octane-3-base, with 8-ethyl-3,8-diazabicyclo [3,2,1] octane-3-base.
The chlorination of the compound of formula I representative normally is dissolved in solvent with compound (I), and in this solution under the refrigerative condition with chlorizating agent.
Be not particularly limited being used for the chlorating solvent, as long as their can molten Jie's starting compounds and are inactive to chlorizating agent.Such solvent comprises halohydrocarbon, for example methylene dichloride, chloroform, tetracol phenixin and 1,2-ethylene dichloride; Alkane carboxylic acid, for example acetate; And formic acid.In addition, also available chlorine sulfonic acid, alcohol (as methyl alcohol, ethanol and propyl alcohol), acetonitrile, N, dinethylformamide, and ethyl acetate.From solvability and promoter action angle, serve as preferred with formic acid and acetate to reacting.
The chlorination of formula I compound both can be carried out in solution, also can carry out in the suspension of formula I compound in solvent, to carry out in solution to preferably.The temperature of chlorination reaction may be up to the reflux temperature of solvent for use, normally carries out (promptly 0 ℃ to 30 ℃) under with the condition of ice-cooled or room temperature.
The consumption of chlorizating agent is generally the 1-2 molar equivalent of starting compound (I).Under with the situation of chlorine as chlorizating agent, general available excessive chlorine.
Chlorination reaction of the present invention is carried out very rapidly, finishes in to 10 hours about 5 minutes greatly, generally finishes in about 5 minutes to 2 hours when ice-cooled.
The 8-chloroquinolone derivatives of formula III can be by gained formula II compound the water of chlorizate be situated between and obtain the R in the formula II 1Be alkyl, it is to carry out with usual method that water is situated between, and for example adopts sour water to be situated between or buck Jie.R when formula II 1Be available C on the phenyl 1-C 6Alkoxyl group, nitro or the chlorine atom replace phenmethyl the time, for example with above-mentioned water Jie method or there is known hydrogen Jie method can remove ester group.
R in the formula II muriate 2When protection amino arranged, this protecting group can be removed with known method, for example uses catalytic reduction method, perhaps the method that sour water is situated between or buck is situated between.
Then needed formula III 8-chloro quinolizidine morpholine derivative is separated (for example using method of extraction) with general chemical process from reaction mixture,, separate recrystallization, and reprecipitation with silica gel column chromatography the extract washing.
Now explain the present invention in more detail with some reference examples and embodiment, but this not should be understood to be the restriction the present invention.All percentage ratios are weight percentage if do not indicate in addition.
Reference example 1
7-(S)-amino-5-azaspiro [2,4] heptane dihydrochloride
6.07g 7-(S)-amino-5-benzyl-5-azaspiro [2,4] heptane, the spissated spirit of salt of 7.5ml and 2.4g concentration in 200ml methyl alcohol be 5% be the palladium catalyst (the 50%th, liquid) of carrier with carbon, this three's mixture was shaken in non-pressurized nitrogen atmosphere 20 hours.The elimination catalyzer under reduced pressure is concentrated into filtrate dry thing, obtains the compound powder of this title of 5.13g.
Fusing point: 222-238 ℃ (divide and be situated between)
[α] D:-43.27 ° (C=0.537, water)
C 8H 12N 2The ultimate analysis of 2HCL:
Calculated value (%): C38.93; H7.62; N15.13
Analytical value (%): C38.83; H7.88; N14.67
1H-NMR(D 2O) δ: 0.9-1.3(4H, m), 3.25 and 3.72(1H, d, J=12.2Hz, each), 3.68 and 3.82(1H, dd, J=12.2,2.9Hz, each), 4.10(1H, dd, J=7.3,6.4Hz)
Reference example 2
7-[7-(S)-amino-5-azaspiro [2,4] heptane-5-yl]-6-fluoro-1-[(1R, 2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid list hydrochloride
In the 85ml acetonitrile, add 4.25g6,7-two fluoro-1-[(1R, 2S)-and 2-fluoro-1-cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid, 3.33g 7-(S)-amino-5-azaspiro [2,4] heptane dihydrochloride and 10.5ml triethylamine heat this mixture 2.5 hours under refluxing.After cooling, filtration is collected established precipitation and it is suspended in the 30ml water, adds the spissated spirit of salt of 2.5ml in this suspension, at room temperature this mixture is stirred 1 hour.Filter the crystallization of collecting in this suspension, wash with water, drying obtains the title compound of 5.81g.
Fusing point: 228-233 ℃ (decomposition)
[α] D：-23.93°（C＝0.449，IN NaOH）
C 19H 19N 3F 2O 3HCl1/2H 2The ultimate analysis of O:
Calculated value (%): C54.22; H5.03; N9.98
Analytical value (%): C53.88; H5.24; N9.64
1H-NMR(NaOD) δ: 0.4-0.8(4H, m), 1.4-1.7(2H, m), 2.97(1H, br s), 3.10 and 3.53(1H, d, J=10.3Hz, each), 3.15-3.3(2H, m), 3.71(1H, br s), 5.05(1H, br d, J=64.0H 2), 6.40(1H, d, J=7.3Hz), and 7.51(1H, d, J=15.1Hz), 8.28(1H, s)
Embodiment 1
7-[7-(S)-uncle-Ding oxygen carbonyl amino-5-azaspiro [2,4] heptane-5-yl]-8-chloro-6-fluoro-1-[(1R, 2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid
Figure 911108335_IMG13
With 120mg7-(7-(S)-uncle-Ding oxygen carbonyl amino-5-azaspiro [2,4] heptane-5-yl)-6-fluoro-1-[(1R, 2S)-and 2-fluoro-1-chloropropyl]-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid is dissolved in the 20ml methylene dichloride, and with the sulfuryl chloride solution of 40mg in the 5ml methylene dichloride, ice-cooled and stir under in the time more than 5 minutes, be added drop-wise to above in the solution.Continue again after dropwising to stir 10 minutes.After confirming that with tlc this raw material has disappeared, this reaction mixture is used saturated sodium bicarbonate aqueous solution and water washing successively, and is dry on anhydrous sodium sulphate again.The methylene dichloride in this mixture is removed in decompression.Residue is by being equipped with the elution post of 10g silica gel, with 9: the title compound that the 1(volume) obtains 101mg after chloroform and the methanol mixture elution.
Fusing point: 223-226 ℃
[α] D:-211.15(C=0.771, chloroform)
C 24H 28ClF 2N 3O 5Ultimate analysis:
Calculated value (%): C56.53; H5.14; N8.24
Analytical value (%): C56.67; H4.95; N8.14
This product 1The H-NMR nuclear magnetic resonance spectrum is identical with the data of this report.
Embodiment 2
7-(7-(S)-amino-5-azaspiro [2,4] heptane-5-yl)-8-chloro-6-fluoro-1-[(1R, 2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid
Figure 911108335_IMG14
In chlorsulfonic acid, under ice-cooled and stirring, add the 7-(7-(S of 120mg)-uncle-Ding oxygen carbonyl amino-5-azaspiro [2,4] heptane-5-yl)-6-fluoro-1-[(1R, 2S)-and 2-fluoro-1-cyclopropyl] 1,4-dihydro-4-Oxoquinoline-3-carboxylic acid adds micro-iodine again.Logical chlorine is 10 minutes in this solution, this mixture is stirred one hour again.This reaction mixture is poured in the frozen water.With furnishing alkalescence of mixture, be adjusted to PH=7 with aqueous citric acid solution with the aqueous sodium hydroxide solution of 1N then.This mixture is with the chloroform extraction of three parts of 50ml, and extractives is dry on anhydrous sodium sulphate.Removal of solvent under reduced pressure, residue is recrystallization from aqueous ethanol, obtains the title compound of 45mg.
Fusing point: 127.3-135.5 ℃
[α] D：-179°（C＝1.12，1N NaOH）
C 19H 18ClF 2N 3O 33/2H 2The ultimate analysis of O:
Calculated value (%): C52.24; H4.85; N9.61
Analytical value (%): C52.16; H4.70; N9.53
Embodiment 3
7-[7-(S)-amino-5-azaspiro [2,4] heptane-5-yl]-8-chloro-6-fluoro-1-[(1R, 2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid
Figure 911108335_IMG15
In 15ml formic acid, dissolve in 3.09g7-[7-(S)-ammonia-5-azaspiro [2,4] heptane-5-yl]-6-fluoro-1-[(1R, 2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid hydrochloride is cooled to this solution 5-10 ℃ solution temperature.Under this temperature, in this solution, slowly splash into 1.25g tert-butyl hypochlorite.After dropwising, this reaction mixture restir 5 minutes is poured in the cold water, neutralizes with 20% aqueous sodium hydroxide solution.Filter the crystallization of collecting precipitation, wash with water, final drying obtains the title compound of 3.02g, is the crystallization of pale yellow.
Molten point: 221-226 ℃ (decomposition)
[α] D：-209.7°（C＝0.631，1N NaOH）
C 19H 18ClF 2N 3O 63/2H 2The ultimate analysis of O:
Calculated value (%): C52.24; H4.85; N9.61
Analytical value (%): C52.31; H4.52; N9.60
This product 1The H-NMR nuclear magnetic resonance spectrum is identical with the data of this report.
Embodiment 4
7-[7-(S)-uncle-Ding oxygen carbonyl amino-5-azaspiro [2,4]-heptane-5-yl]-8-chloro-6-fluoro-1-[(1R, 2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid
Figure 911108335_IMG16
In the 5ml methylene dichloride, dissolve in 238mg7-[7-(S)-uncle-Ding oxygen carbonyl amino-5-azaspiro [2,4] heptane-5-yl]-6-fluoro-1-[(1R, 2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid is at the ice-cooled 80mg tert-butyl hypochlorite that slowly drips down.After dropwising, under this temperature with mixture restir 2 hours.Reaction mixture is used 5% aqueous citric acid solution and water washing successively, and removal of solvent under reduced pressure obtains the title compound powder of 217mg, is pale yellow.
Fusing point: 220-224 ℃
[α] D:-208.31 ℃ (C=0.683, chloroform)
C 24H 26ClF 2N 3O 6Ultimate analysis:
Calculated value (%): C56.53; H5.14; N8.24
Analytical value (%): C56.21; H5.04; N8.31
This product 1The H-NMR nuclear magnetic resonance spectrum is identical with this report data.
According to the present invention,, can obtain the 8-chloroquinolone derivatives that productive rate is satisfied, purity is high by easy operation with the unsubstituted Carbostyril derivative chlorination of 8-.Especially when an amino is arranged in the molecule of raw material Carbostyril derivative as substituting group, just can obtain chlorination as chlorizating agent, also guarantee satisfied productive rate and degree of purity of production simultaneously not protecting amino this compound with the hypochlorous acid ester.
Though the present invention has been done detailed explanation, obviously can do various changes and change to those of ordinary skill in the art and do not depart from design of the present invention and scope to the present invention with specific example.

Claims (17)

1, a kind of method for preparing the 8-chloroquinolone derivatives of formula II representative,
Figure 911108335_IMG2
X in the formula II represents halogen atom; R 1Represent hydrogen atom, C 1-C 6Alkyl or phenyl part the benzene alkyl of nitro, chlorine atom or alkoxyl group can be arranged; R 2Represent a saturated heterocyclic radical of 4-8 unit that contains one or two nitrogen-atoms as annular atoms, this heterocyclic radical also can further contain a Sauerstoffatom and sulphur atom as annular atoms and one or more substituting groups can be arranged, and this substituting group is selected from following this group group: amino, at moieties one alkylamino of 1-6 carbon atom or dialkyl amido, C are arranged 2-C 7Alkyl-carbonyl-amino, C 2-C 7Alkoxycarbonyl amino, C 2-C 7Halogenated alkyl carbonyl, C 2-C 7Halo alkoxy carbonyl amino, phenyl alkoxycarbonyl amino, the C of a nitro or a chlorine atom can be arranged at phenyl moiety 1-C 8Alkyl, form the C of a volution with the carbon atom that constitutes heterocyclic radical 2-C 8Alkylidene group, halogen atom and C 1-C 8Alkoxyl group, this method comprises quinolone compounds and the chlorination reaction with formula (I),
Figure 911108335_IMG3
X, R in the formula 1And R 2Definition same as described above.
2, a kind of method for preparing by the 8-chloroquinolone derivatives of formula III representative,
Figure 911108335_IMG4
X represents halogen atom in the formula; R 3Representative contains the saturated heterocyclyl of one or two nitrogen-atoms as the 4-8 unit of annular atoms, this heterocyclic radical also can further contain oxygen or sulphur atom as an annular atoms and one or more substituting groups can be arranged, and this substituting group is selected from next group group: amino, at moieties one alkylamino of 1-6 carbon atom or dialkyl amido, C are arranged 1-C 6Alkyl form the C of a volution with the carbon atom that constitutes heterocyclic radical 2-C 8Alkylidene group, halogen atom and C 1-C 2Alkoxyl group, this method comprise and the protecting group of formula II compound being removed and/or the hydrolysis of ester group,
Figure 911108335_IMG5
X represents halogen atom in the formula; R 1Represent hydrogen atom or C 1-C 6Alkyl; R 2Representative contains one or two nitrogen-atoms saturated heterocyclyl as the 4-8 unit of annular atoms, and this heterocyclic radical also can further contain oxygen or sulphur atom as an annular atoms and one or more substituting groups that are selected from following this group group can be arranged: amino, at moieties one alkylamino of 1-6 carbon atom or dialkyl amido, C are arranged 2-C 7Alkyl-carbonyl-amino, C 2-C 7Alkoxycarbonyl amino, C 2-C 7Halogenated alkyl carbonyl, C 2-C 7Halo alkoxy carbonyl amino, phenyl alkoxycarbonyl amino, the C of a nitro or chlorine atom can be arranged at phenyl moiety 1-C 8Alkyl, form the C of a volution with the carbon atom that constitutes heterocyclic radical 2-C 6Alkylidene group, halogen atom and C 1-C 6Alkoxyl group.
3, the process of claim 1 wherein that said chlorizating agent is selected from sulfuryl chloride, clorox, N-chlorosuccinimide and chlorine.
4, the process of claim 1 wherein that said oxygenant is the hypochlorous acid ester by the formula IV representative:
R in the formula 4Represent C 1-6Alkyl, benzene alkyl or chlorobenzene alkyl.
5, the method for claim 4, wherein R 4Be sec.-propyl, tert-butyl or benzyl.
6, the method for claim 4, wherein R 4It is tert-butyl.
7, the process of claim 1 wherein R 2Be 7-amino-5-azaspiro [2,4] heptane-5-base, 8-amino-6-azaspiro [3,4] octane-6-base, 3,3-dimethyl-4-amino-pyrroles alkyl or 3-amino-pyrroles alkyl.
8, the method for claim 2, wherein R 2Be 7-amino-5-azaspiro [2,4] heptane-5-base, 8-amino-6-azaspiro [3,4] octane-6-base, 3,3-dimethyl-4-amino-pyrroles alkyl or 3-amino-pyrroles alkyl.
9, the process of claim 1 wherein that said formula I compound is a kind of compound by the following formula representative.
Figure 911108335_IMG6
R in the formula 1Identical with in the definition of X and the claim 1.
10, the process of claim 1 wherein that said formula I compound is a kind of compound by the following formula representative.
Figure 911108335_IMG7
R in the formula 1Identical with in the definition of X and the claim 1.
11, the process of claim 1 wherein that said formula I compound is a kind of compound of following formula representative.
Figure 911108335_IMG8
R in the formula 1Identical with X and claim 1.
12, the process of claim 1 wherein that said formula II compound is 7-[7-amino-5-azaspiro [2,4] heptane-5 base]-8-chloro-6-fluoro-1-(1,2-cis-2-fluorine cyclopropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or its ester.
13, the process of claim 1 wherein that said formula II compound is a 7-(3-amino-pyrroles alkyl)-8-chloro-6-fluoro-1-(1,2-cis-2-fluorine cyclopropyl)-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid or its ester.
14, the process of claim 1 wherein that said formula II compound is 7-[7-(S)-amino-5-azaspiro [2,4] heptane-5 base]-8-chloro-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or its ester.
15, the process of claim 1 wherein that said formula II compound is 7-[3-(S)-the amino-pyrroles alkyl]-8-chloro-6-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid or its ester.
16, the method for claim 1, wherein said formula I compound is 7-[7-amino-5-azaspiro [2,4] heptane-5-yl]-6-fluoro-1-(1,2-cis-2-fluorine cyclopropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or its ester, said chlorizating agent is the tert-butyl hypochlorite, and said formula II compound is 7-[7-amino-5-azaspiro [2,4] heptane-5-yl]-8-chloro-6-fluoro-1-(1,2-cis-2-fluorine cyclopropyl)-and 4-oxo-1,4-dihydroquinoline-3-carboxylic acid or its ester.
17, the method for claim 1, wherein said formula I compound is 7-[7-(S)-amino-5-azaspiro [2,4] heptane-5-yl]-6-fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid or its ester, said chlorizating agent is the tert-butyl hypochlorite, and said formula II compound is 7-[7-(S)-amino-5-azaspiro [2,4] heptane-5-yl]-8-chloro-6-fluoro-1-[(1R, 2S)-and 2-fluorine cyclopropyl]-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid or its ester.
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EP0593766A4 (en) * 1991-05-28 1994-12-07 Daiichi Seiyaku Co Pyridonecarboxylic acid derivative.
EP0643058A1 (en) * 1993-09-10 1995-03-15 Daiichi Pharmaceutical Co., Ltd. Crystals of an antimicrobial compound
WO2003014108A1 (en) * 2001-08-08 2003-02-20 Institute Of Medicinal Biotechnology Chinese Academy Of Medical Sciences New quinoline carboxylic acid derivatives substituted by 7-(aminomethyl-5-azospiro[2,4]heptane) and their prepartion method
CN103483315A (en) * 2013-09-18 2014-01-01 浙江司太立制药股份有限公司 7-(3-aminomethyl-4-alkoxyimino-1-piperidyl)-1-[(1R,2S)-2-fluorocyclopropyl] quinolone carboxylic acid compounds and preparation method thereof
CN103709100A (en) * 2013-12-31 2014-04-09 南京工业大学 Preparation method of 8-chloroquinolone derivatives
CN104892600A (en) * 2015-06-04 2015-09-09 浙江司太立制药股份有限公司 7-(3-aminomethyl-4-substituted-benzyloxyimino-1-pyrrolidinyl)naphthyridinone carboxylic acid compounds
CN105061395A (en) * 2015-08-10 2015-11-18 江苏吴中医药集团有限公司 Preparation method for sitafloxacin hydrate
CN105669646A (en) * 2016-02-26 2016-06-15 济川药业集团有限公司 Synthesis method of sitafloxacin hydrate
CN113527200A (en) * 2021-05-27 2021-10-22 北京斯利安药业有限公司 Preparation method of chloroquinate

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EP0593766A4 (en) * 1991-05-28 1994-12-07 Daiichi Seiyaku Co Pyridonecarboxylic acid derivative.
EP0643058A1 (en) * 1993-09-10 1995-03-15 Daiichi Pharmaceutical Co., Ltd. Crystals of an antimicrobial compound
US5693814A (en) * 1993-09-10 1997-12-02 Daiichi Pharmaceutical Co., Ltd. Crystals of antimicrobial compound
CN1057297C (en) * 1993-09-10 2000-10-11 第一制药株式会社 Crystals of antimicrobial compound
WO2003014108A1 (en) * 2001-08-08 2003-02-20 Institute Of Medicinal Biotechnology Chinese Academy Of Medical Sciences New quinoline carboxylic acid derivatives substituted by 7-(aminomethyl-5-azospiro[2,4]heptane) and their prepartion method
CN103483315A (en) * 2013-09-18 2014-01-01 浙江司太立制药股份有限公司 7-(3-aminomethyl-4-alkoxyimino-1-piperidyl)-1-[(1R,2S)-2-fluorocyclopropyl] quinolone carboxylic acid compounds and preparation method thereof
CN103483315B (en) * 2013-09-18 2015-07-01 浙江司太立制药股份有限公司 7-(3-aminomethyl-4-alkoxyimino-1-piperidyl)-1-[(1R,2S)-2-fluorocyclopropyl] quinolone carboxylic acid compounds and preparation method thereof
CN103709100A (en) * 2013-12-31 2014-04-09 南京工业大学 Preparation method of 8-chloroquinolone derivatives
CN104892600A (en) * 2015-06-04 2015-09-09 浙江司太立制药股份有限公司 7-(3-aminomethyl-4-substituted-benzyloxyimino-1-pyrrolidinyl)naphthyridinone carboxylic acid compounds
CN105061395A (en) * 2015-08-10 2015-11-18 江苏吴中医药集团有限公司 Preparation method for sitafloxacin hydrate
CN105669646A (en) * 2016-02-26 2016-06-15 济川药业集团有限公司 Synthesis method of sitafloxacin hydrate
CN113527200A (en) * 2021-05-27 2021-10-22 北京斯利安药业有限公司 Preparation method of chloroquinate

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