CN103360310B - The preparation method of a kind of Sitafloxacin intermediate, Sitafloxacin and sitafloxacin medicine composition - Google Patents
The preparation method of a kind of Sitafloxacin intermediate, Sitafloxacin and sitafloxacin medicine composition Download PDFInfo
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Abstract
The invention discloses a kind of Sitafloxacin intermediate, the preparation method of Sitafloxacin and the pharmaceutical composition containing Sitafloxacin.Preparation method of the present invention solves existing Sitafloxacin intermediate and is preparing the problem that the productive rate existed in Sitafloxacin process is low, aftertreatment trouble, poor stability and cost are higher.Preparation method's technique of the present invention is simple, and raw material is easy to get, and cost is lower, and after reaction, solvent is easy to process, and yield is high, very suitability for mass industrialized production.The sitafloxacin medicine composition that preparation method provided by the invention obtains, can further improve the result of extraction of product, improves Sitafloxacin bioavailability in vivo simultaneously, enhances the performance of drug effect.
Description
Technical field
The present invention relates to a kind of Sitafloxacin intermediate, the preparation method of Sitafloxacin and the pharmaceutical composition containing Sitafloxacin.
Background technology
Sitafloxacin (sitafloxacin), chemistry 7-[(7S)-amino-5-azaspiro [2.4]-5-in heptan base] fluoro-the 1-[(1R of the chloro-6-of-8-by name, 2S)-cis-2-fluorine cyclopropyl]-1,4-dihydro-4-oxo-3-quinoline carboxylic acid, be the fluoroquinolones antiseptic-germicide of Japanese first drugmaker research and development, clinically use its monohydrate.Sitafloxacin is a kind of new oral, has the N-1-fluorine cyclopropyl novel carbostyril antimicrobial drug of broad spectrum antibiotic activity, has broad-spectrum antibacterial action to aerobism or anaerobism gram positive organism and gram-negative bacteria, Mycoplasma and chlamydiaceae etc.
About the synthesis of this compound, the people such as Japanese YouichiKimura were in its synthetic route of (J.Med.Chem.1994.37 (20), 3344-3352) reported first in 1994.The document discloses with 2,4,5-trifluoromethyl benzonitrile ethyl acetoacetic acid ethyl ester and 2,4,5-tri-fluoro-3-chlorobenzoyl ethyl acetate is that starting material synthesizes, and synthetic route is as follows:
.
In the synthetic route of document report, its key intermediate 2-(3-chloro-2, 4, 5-trifluoromethylbenzoyl)-3-(1R, 2S)-2-fluoro cyclopropane is amino] ethyl propenoate (14a) synthesizes another key intermediate 8-chloro-6, fluoro-the 1-[(1R of 7-bis-, 2S)-2-fluoro cyclopropane base]-4-oxo-1, time 4-dihydroquinoline-3-carboxylic acid, ethyl ester (15a), its reaction conditions is with sodium hydrogen (NaH) Guan Huan in dioxane (i.e. diox), this reaction conditions is very harsh, need to control moisture and temperature of reaction, and sodium hydrogen very easily fires, poor stability, dioxane is toxicant, environmental pollution is very large, cost is high, be unfavorable for suitability for industrialized production.
The people such as Japan ShohgoAtarashi were in (J.Med.Chem.1993.36 (20) in 1993,3444-3448) disclose the intermediate 6 for the synthesis of Sitafloxacin, fluoro-the 1-[(1R of 7-bis-, 2S)-2-fluoro cyclopropane base]-4-oxo-1, the synthetic method of 4-dihydroquinoline-3-carboxylic acid, ethyl ester (18), synthetic route is as follows:
。
This synthetic method not only used NaH and diox, and synthesis yield lower (78%), is extremely unfavorable for suitability for industrialized production.
Summary of the invention
The object of the invention is to overcome existing Sitafloxacin intermediate preparing that the productive rate existed in Sitafloxacin process is low, aftertreatment is complicated, poor stability and the higher problem of cost, provide the synthetic method that a kind of Sitafloxacin intermediate is new.Use that this Intermediate Preparation Sitafloxacin yield is high, security is high, cost is low, be easy to realize suitability for industrialized production, be also easy to configuration and the use of pharmaceutical composition simultaneously.
Another object of the present invention is to provide a kind of preparation method by described Intermediate Preparation Sitafloxacin.
Another object of the present invention is to provide a kind of containing the pharmaceutical composition by the Sitafloxacin of described Intermediate Preparation.
Object of the present invention is achieved through the following technical solutions:
The preparation method that Sitafloxacin intermediate is new, is characterized in that described preparation method comprises the following step:
(1) by raw material (
iI) be dissolved in polar solvent, add Lewis base reaction, thin-layer chromatography (TLC) monitoring is to reacting completely;
(2) by polar solvent remove, obtain Sitafloxacin intermediate (
);
Wherein R is hydrogen, halogen.
Described polar solvent comprises aprotic polar solvent and protonic solvent, wherein said aprotic polar solvent refers to that itself not easily provides proton, there is again the solvent of very strong dissolving power, include but not limited to N, dinethylformamide, N,N-dimethylacetamide, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), acetone etc.; Described protonic solvent refers to and can provide hydrionic solvent, includes but not limited to methyl alcohol, ethanol, acetonitrile, Virahol etc.
Described Lewis base is pharmaceutically can use Lewis base, includes but not limited to NaOH, KOH, LiOH, triethylamine, diethylamine, ammoniacal liquor, salt of weak acid etc.The negatively charged ion generated when described salt of weak acid is ionization is the salt of weak acid radical ion, includes but not limited to Li
2cO
3, Na
2cO
3, K
2cO
3, Cs
2cO
3, LiHCO
3, NaHCO
3, KHCO
3, CsHCO
3, sodium-acetate, Potassium ethanoate, sodium oxalate, potassium oxalate etc.
Described halogen is selected from fluorine, chlorine, bromine or iodine.
A preparation method for Sitafloxacin, is characterized in that described preparation method comprises the following step:
(1) by Sitafloxacin intermediate (
iI) (wherein R is chlorine) be dissolved in polar solvent, adds Lewis base reaction, polar solvent, to reacting completely, is removed by thin-layer chromatography monitoring, obtain Sitafloxacin intermediate (
) (wherein R is chlorine), i.e. chloro-6, the 7-bis-fluoro-1-of 8-[(1R, 2S)-2-fluoro cyclopropane base]-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-carboxylic acid, ethyl ester;
(2) 8-chloro-6, fluoro-the 1-[(1R of 7-bis-, 2S)-2-fluoro cyclopropane base]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, ethyl ester through hydrolysis after with intermediate five-ring 7-(s)-t-butoxycarbonyl amino-azaspiro [2,4] heptane is obtained by reacting compound 7-[7-(s)-tertbutyloxycarbonyl-5-azaspiro [2,4] heptane-5-base] fluoro-the 1-[(1R of the chloro-6-of-8-, 2S) the fluoro-1-cyclopropyl of-2-]-Isosorbide-5-Nitrae-dihydro-4-Oxoquinoline-3-carboxylic acid;
(3) 7-[7-(s)-tertbutyloxycarbonyl-5-azaspiro [2; 4] heptane-5-base] fluoro-the 1-[(1R of the chloro-6-of-8-; 2S) the fluoro-1-cyclopropyl of-2-]-Isosorbide-5-Nitrae-dihydro-4-Oxoquinoline-3-carboxylic acid obtains Sitafloxacin finished product after trifluoroacetic acid deprotection, crystal refining.
Described polar solvent comprises aprotic polar solvent and protonic solvent, wherein said aprotic polar solvent refers to that itself not easily provides proton, there is again the solvent of very strong dissolving power, include but not limited to N, dinethylformamide, N,N-dimethylacetamide, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), acetone etc.; Described protonic solvent refers to and can provide hydrionic solvent, includes but not limited to methyl alcohol, ethanol, acetonitrile, Virahol etc.
Described Lewis base is pharmaceutically can use Lewis base, includes but not limited to NaOH, KOH, LiOH, triethylamine, diethylamine, ammoniacal liquor, salt of weak acid etc.The negatively charged ion generated when described salt of weak acid is ionization is the salt of weak acid radical ion, includes but not limited to Li
2cO
3, Na
2cO
3, K
2cO
3, Cs
2cO
3, LiHCO
3, NaHCO
3, KHCO
3, CsHCO
3, sodium-acetate, Potassium ethanoate, sodium oxalate, potassium oxalate etc.
A kind of sitafloxacin medicine composition, said composition is made up of Sitafloxacin and one or more pharmaceutically acceptable carriers and/or vehicle, it is characterized in that: described pharmaceutical composition is prepared by the following method:
(1) by the preparation method described in the arbitrary claim of claim 1-6 prepare Sitafloxacin intermediate (
), by this Sitafloxacin intermediate (
) prepare Sitafloxacin;
(2), in the pharmaceutically acceptable carrier needed when being joined and prepare different pharmaceutical preparation formulation by the Sitafloxacin obtained in step (1) and/or vehicle, sitafloxacin medicine composition is obtained.
A kind of sitafloxacin medicine composition, said composition is made up of Sitafloxacin and one or more pharmaceutically acceptable carriers and/or vehicle, it is characterized in that: described pharmaceutical composition is prepared by the following method:
(1) by Sitafloxacin intermediate (
iI) be dissolved in polar solvent, described Sitafloxacin intermediate (
iI) R substituent be chlorine, add Lewis base reaction, thin-layer chromatography monitoring is to reacting completely, polar solvent is removed, obtain Sitafloxacin intermediate (I), i.e. chloro-6,7-bis-fluoro-the 1-[(1R of 8-, 2S)-2-fluoro cyclopropane base]-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-carboxylic acid, ethyl ester;
(2) 8-chloro-6, fluoro-the 1-[(1R of 7-bis-, 2S)-2-fluoro cyclopropane base]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, ethyl ester through hydrolysis after with intermediate five-ring 7-(s)-t-butoxycarbonyl amino-azaspiro [2,4] heptane is obtained by reacting compound 7-[7-(s)-tertbutyloxycarbonyl-5-azaspiro [2,4] heptane-5-base] fluoro-the 1-[(1R of the chloro-6-of-8-, 2S) the fluoro-1-cyclopropyl of-2-]-Isosorbide-5-Nitrae-dihydro-4-Oxoquinoline-3-carboxylic acid;
(3) 7-[7-(s)-tertbutyloxycarbonyl-5-azaspiro [2,4] heptane-5-base] fluoro-the 1-[(1R of the chloro-6-of-8-, 2S) the fluoro-1-cyclopropyl of-2-]-Isosorbide-5-Nitrae-dihydro-4-Oxoquinoline-3-carboxylic acid obtains Sitafloxacin after trifluoroacetic acid deprotection, crystal refining;
(4), in the pharmaceutically acceptable carrier needed when being joined and prepare different pharmaceutical preparation formulation by the Sitafloxacin obtained in step (3) and/or vehicle, sitafloxacin medicine composition is obtained.
Above-mentioned pharmaceutically acceptable carrier and/or vehicle comprise the mixture of one or more above-mentioned substances in weighting agent, tackiness agent, disintegrating agent, dispersion agent, tinting material, softening agent, sanitas, lubricant, sweeting agent, solubilizing agent, spices etc.
Described sitafloxacin medicine composition go for oral, suck, parenteral routes or surface use; Formulation includes but not limited to injection, pharmaceutical solutions, tablet, capsule, granule etc.; Can effectively for the treatment of other bacteriological infection such as urinary tract infections, respiratory tract infection, skin soft-tissue infection in curative effect.
Described sitafloxacin medicine composition can adopt conventional pharmaceutical preparation preparation method to be prepared into common medicament form of pharmaceutical preparation as injection, pharmaceutical solutions, tablet, capsule, granule etc.
Compared to the prior art, the present invention has following advantage and beneficial effect:
1, preparation method of the present invention adopt polar solvent replacing diox, replace with Lewis base NaH prepare Sitafloxacin intermediate (
), solve in prior art and use NaH Yu the diox poor stability, aftertreatment is complicated and cost the is higher problem that cause, preparation method's technique of the present invention is simple, raw material is easy to get, cost is lower, and after reaction, solvent is easy to process, very suitability for mass industrialized production.
2, technical scheme of the present invention solves in prior art and prepares the low problem of Sitafloxacin intermediate productive rate.From compound (
iI) to compound (
) two step compound experiments show, the present invention by select synthesis polar solvent used particularly aprotic polar solvent (as N, dinethylformamide, tetrahydrofuran (THF), N,N-dimethylacetamide, acetone, dimethyl sulfoxide (DMSO) etc.) or protonic solvent (such as methyl alcohol etc.) and Lewis base (as Na
2cO
3, triethylamine, NaHCO
3, KOH, LiHCO
3deng) carry out realization response time yield than existing Sitafloxacin Intermediate Preparation technique (J.Med.Chem.1993.36 (20), yield 3444-3448) improves about 10%, cost has greatly been saved in industrialized production, simultaneously solvent used and Lewis base cheap and easy to get, stable in properties, security is good, recyclable after reaction, aftertreatment is simple, is easy to suitability for industrialized production.
3, adopting method of the present invention to prepare, Sitafloxacin yield is high, security is high, cost is low, be easy to realize suitability for industrialized production.
4, adopt the preparation-obtained Sitafloxacin of method of the present invention due to superior product quality, stable in properties, making it when preparing sitafloxacin medicine composition, being easy to the configuration in pharmaceutical composition and use, make sitafloxacin medicine composition stable in properties.
5, the sitafloxacin medicine composition that obtains of preparation method provided by the invention, can further improve the result of extraction of product, improves Sitafloxacin bioavailability in vivo simultaneously, enhance the performance of drug effect.Cost of supplementary product used is in addition low, and preparation method is simple, composition stable in properties, is applicable to suitability for industrialized production.
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail, but working of an invention mode is not limited thereto.
The preparation of chloro-6, the 7-bis-fluoro-1-of embodiment 18-[(1R, 2S)-2-fluoro cyclopropane base]-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-carboxylic acid, ethyl ester
Get chloro-2,4, the 5-trifluoromethylbenzoyl of 2-(3-)-3-(1R, 2S)-2-fluoro cyclopropane is amino] ethyl propenoate 3.65g is dissolved in 40mlN, in dinethylformamide (DMF), adds 3.18gNa
2cO
3, be stirred and heated to 40 DEG C, TLC monitoring reaction is to raw material point disappearance stopped reaction, and DMF decompression be spin-dried for, add 50ml water and the phase-splitting of 100ml methylene dichloride, organic layer is spin-dried for, dry product 3.2g, yield 92.7%.Fusing point: 179.5-181 DEG C, m/e346.7 [M+H]
+,
1h-NMR (500MHz, DMSO) δ (ppm): 8.64 (d, J=2.5,1H), 8.13 (m, 1H), 5.11 (m, 1H), 4.30 (m, 2H), 4.23 (m, 1H), 1.72 (m, 2H), 1.33 (t, J=7.5,3H).
The preparation of fluoro-6, the 7-bis-fluoro-1-of embodiment 28-[(1R, 2S)-2-fluoro cyclopropane base]-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-carboxylic acid, ethyl ester
Get fluoro-2,4, the 5-trifluoromethylbenzoyl of 2-(3-)-3-(1R; 2S)-2-fluoro cyclopropane is amino] ethyl propenoate 3.49g is dissolved in 40ml tetrahydrofuran (THF); add 2.8ml triethylamine, stirring heating refluxes, and TLC monitoring reaction is to raw material point disappearance stopped reaction; tetrahydrofuran (THF) is spin-dried for; add 50ml water and the phase-splitting of 100ml methylene dichloride, organic layer is spin-dried for, dry product 2.87g; yield 87%, m/e330.3 [M+H]
+,
1h-NMR (500MHz, DMSO) δ (ppm): 8.54 (d, J=2.5,1H), 8.23 (m, 1H), 5.21 (m, 1H), 4.30 (m, 2H), 4.33 (m, 1H), 1.82 (m, 2H), 1.34 (t, J=7.5,3H).
The preparation of the fluoro-1-of embodiment 36,7-bis-[(1R, 2S)-2-fluoro cyclopropane base]-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-carboxylic acid, ethyl ester
Get 2-(2,4,5-trifluoromethylbenzoyl)-3-(1R; 2S)-2-fluoro cyclopropane is amino] ethyl propenoate 3.31g is dissolved in 50mlN, in N-N,N-DIMETHYLACETAMIDE (DMA), adds 9.7g potassium oxalate; be stirred and heated to 50 DEG C, DMA decompression, to raw material point disappearance stopped reaction, is spin-dried for by TLC monitoring reaction; add 50ml water and the phase-splitting of 100ml methylene dichloride; organic layer is spin-dried for, dry product 2.7g, yield 86.8%; fusing point: 249-251 DEG C, m/e312.2 [M+H]
+,
1h-NMR (500MHz, DMSO) δ (ppm): 8.66 (d, J=2.5,1H), 8.25 (m, 1H), 8.15 (m, 1H), 5.13 (m, 1H), 4.32 (m, 2H), 4.25 (m, 1H), 1.75 (m, 2H), 1.35 (t, J=7.5,3H).
The preparation of bromo-6, the 7-bis-fluoro-1-of embodiment 48-[(1R, 2S)-2-fluoro cyclopropane base]-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-carboxylic acid, ethyl ester
Get 2-(3-bromo-2,4,5-trifluorobenzene formyl radical)-3-(1R, 2S)-2-fluoro cyclopropane is amino] ethyl propenoate 4.1g is dissolved in 80ml acetone, adds 4.3gNaHCO
3, stirring heating refluxes, and TLC monitoring reaction is to raw material point disappearance stopped reaction, and be spin-dried for by acetone, add 50ml water and the phase-splitting of 100ml methylene dichloride, organic layer is spin-dried for, dry product 3.51g, yield 90%, m/e391.2 [M+H]
+,
1h-NMR (500MHz, DMSO) δ (ppm): 8.66 (d, J=2.5,1H), 8.45 (m, 1H), 8.15 (m, 1H), 5.16 (m, 1H), 4.33 (m, 2H), 4.35 (m, 1H), 1.85 (m, 2H), 1.35 (t, J=7.5,3H).
The preparation of iodo-6, the 7-bis-fluoro-1-of embodiment 58-[(1R, 2S)-2-fluoro cyclopropane base]-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-carboxylic acid, ethyl ester
Get iodo-2,4, the 5-trifluoromethylbenzoyl of 2-(3-)-3-(1R; 2S)-2-fluoro cyclopropane is amino] ethyl propenoate 4.6g is dissolved in 40mL dimethyl sulfoxide (DMSO); add 0.6gKOH, stirring heating refluxes, and TLC monitoring reaction is to raw material point disappearance stopped reaction; dimethyl sulfoxide (DMSO) is spin-dried for; add 50ml water and the phase-splitting of 100ml methylene dichloride, organic layer is spin-dried for, dry product 3.93g; yield 89.5%, m/e438.2 [M+H]
+,
1h-NMR (500MHz, DMSO) δ (ppm): 8.67 (d, J=2.5,1H), 8.65 (m, 1H), 8.15 (m, 1H), 5.13 (m, 1H), 4.32 (m, 2H), 4.45 (m, 1H), 1.95 (m, 2H), 1.35 (t, J=7.5,3H).
The preparation of the fluoro-1-of embodiment 66,7-bis-[(1R, 2S)-2-fluoro cyclopropane base]-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-carboxylic acid, ethyl ester
Get 2-(2,4,5-trifluoromethylbenzoyl)-3-(1R, 2S)-2-fluoro cyclopropane is amino] ethyl propenoate 3.3g is dissolved in 60ml methyl alcohol, adds 3.9gLiHCO
3, stirring heating refluxes, and TLC monitoring reaction is to raw material point disappearance stopped reaction, and be spin-dried for by methyl alcohol, add 50ml water and the phase-splitting of 100ml methylene dichloride, organic layer is spin-dried for, dry product 2.8g, yield 90%, fusing point: 249-251 DEG C, m/e312.2 [M+H]
+,
1h-NMR (500MHz, DMSO) δ (ppm): 8.66 (d, J=2.5,1H), 8.25 (m, 1H), 8.15 (m, 1H), 5.13 (m, 1H), 4.32 (m, 2H), 4.25 (m, 1H), 1.75 (m, 2H), 1.35 (t, J=7.5,3H).
The preparation of embodiment 77-[7-(s)-tertbutyloxycarbonyl-5-azaspiro [2,4] heptane-5-base] the fluoro-1-of the chloro-6-of-8-[the fluoro-1-cyclopropyl of (1R, 2S)-2-]-Isosorbide-5-Nitrae-dihydro-4-Oxoquinoline-3-carboxylic acid
Get chloro-6, the 7-bis-fluoro-1-of 8-[(1R, 2S)-2-fluoro cyclopropane base]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, ethyl ester 0.5g is dissolved in 300ml concentrated hydrochloric acid, stirs lower reflux, reaction 3h, TLC monitoring, to reacting completely, is chilled to room temperature, and the sodium hydroxide solution adding 30% adjusts pH value 3 ~ 4, use dichloromethane extraction twice again, merge organic phase, anhydrous sodium sulfate drying, filter, concentrated filtrate obtains solid, then is directly used in next step with after ethyl alcohol recrystallization.
Above-mentioned solid and 7-(s)-t-butoxycarbonyl amino-azaspiro [2,4] heptane 4.3g being mixed adds in 500ml acetonitrile solution, drips triethylamine 8.8ml, is heated with stirring to 80 DEG C of back flow reaction 2h, TLC and tracks to and react completely.Removal of solvent under reduced pressure, adds 200ml methylene dichloride in residue, then uses water, saturated common salt water washing respectively.Merge organic phase, anhydrous sodium sulfate drying, filter, concentrated filtrate obtains product 0.62g, yield 81%, fusing point: 224.7-225.6 DEG C, m/e510.8 [M+H]
+, 1H-NMR (500MHz, DMSO) δ (ppm): 8.74 (d, J=4.0,1H), 7.82 (d, J=17,1H), 7.26 (d, J=9,1H), 5.20 (m, 0.5H), 5.04 (m, 0.5H), 4.27 (m, 2H), 4.20 (m, 1H), 3.76 (m, 1H), 3.24 (m, 2H), 1.63 (m, 1H), 1.38 (s, 9H), 0.68 (m, 1H), 0.66 (m, 2H), 0.62 (m, 1H).
The preparation of embodiment 8 Sitafloxacin
Get 0.55g7-[7-(s)-tertbutyloxycarbonyl-5-azaspiro [2, 4] heptane-5-base] fluoro-the 1-[(1R of the chloro-6-of-8-, 2S) the fluoro-1-cyclopropyl of-2-]-1, 4-dihydro-4-Oxoquinoline-3-carboxylic acid adds round-bottomed flask, add 20ml trifluoroacetic acid again, 1ml methyl-phenoxide, 0 ~ 10 DEG C of reaction, TLC monitoring reaction is to complete, pressurization is concentrated, adding 20% sodium hydroxide solution in residue adjusts pH value to 11-12, add 50ml methylene dichloride, 40ml sodium hydroxide solution is added in stirring, merge buck layer, washed with dichloromethane, merge buck, adjust pH value to 6-7 with dilute hydrochloric acid, stirred crystallization, obtain crude product.
Above-mentioned crude product is added distilled water 4ml, dehydrated alcohol 2ml, 28% ammoniacal liquor 0.5ml, 45 DEG C of heating for dissolving add activated carbon decolorizing, filter, filtrate stirs 3-4 hour at 45 DEG C, and cooling crystallization, obtains product 0.43g, yield 91.5%, fusing point: 225 DEG C of decomposition, m/e366.8 [M+H]
+,
1h-NMR (500MHz, DMSO) δ (ppm): 0.50(m, 1H), 0.60(m, 2H), 0.84(m, 1H), 1.39(m, 0.5H), 1.44(m, 0.5H), 1.64(m, 1H), 3.31(m, 1H), 3.33(m, 2H), 4.05(m, 1H), 4.12(m, 1H), 4.29 (m, 1H), 5.02(m, 0.5H), 5.15(m, 0.5H), 7.80 (d, J=13.5,1H), 8.73 (d, J=3,1H).
The preparation of embodiment 9 sitafloxacin medicine composition
Prescription: Sitafloxacin 50mg
Microcrystalline Cellulose 78mg
Hydroxypropylcellulose 15mg
Cross-linked polyvinylpyrrolidone 4mg
Magnesium Stearate 5mg
The Sitafloxacin prepare embodiment 8 and each component auxiliary material put into mixer granulator, stirring at low speed and shear-mixed after weighing, and mixture sieves, and adopt dry granulation, drying, add lubricant, compressing tablet, obtain Sitafloxacin tablet.
Above-described embodiment is the present invention's preferably embodiment; but embodiments of the present invention are not restricted to the described embodiments; change, the modification done under other any does not deviate from spirit of the present invention and principle, substitute, combine, simplify; all should be the substitute mode of equivalence, be included within protection scope of the present invention.
Claims (1)
1. the preparation method of a Sitafloxacin intermediate, it is characterized in that described preparation method comprises the following step: get 2-(2, 4, 5-trifluoromethylbenzoyl)-3-[(1R, 2S)-2-fluoro cyclopropane is amino] ethyl propenoate 3.3g is dissolved in 60ml methyl alcohol, add 3.9gLiHCO3, stirring heating refluxes, TLC monitoring reaction is to raw material point disappearance stopped reaction, methyl alcohol is spin-dried for, add 50ml water and the phase-splitting of 100ml methylene dichloride, organic layer is spin-dried for, dry Sitafloxacin intermediate 6, fluoro-the 1-[(1R of 7-bis-, 2S)-2-fluoro cyclopropane base]-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid, ethyl ester.
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