CN104031063A - Quinolone compound as well as preparation method and application thereof - Google Patents
Quinolone compound as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a quinolone compound as well as a preparation method and application thereof. The quinolone compound has a structural formula as shown in the specification. The preparation method comprises the following steps: performing cyanation reaction on (S)-9,10-difluoro-3-methyl-2,3-dihydro-7-oxo-7H-pyridino[1,2,3-de] [1,4]benzoxazine-6-ethyl carboxylate (2) and NaCN at 30-100 DEG C to obtain a reaction solution, filtering the reaction solution to obtain a filter cake, adding water for pulping, leaching by using water, filtering, and drying to obtain the quinolone compound. The quinolone compound is hydrolyzed to obtain pazufloxacin impurities shown in a formula which is as shown in the specification, and can be used for pathological toxicological research of drug side effects of pazufloxacin. The quinolone compound is conductive to explaining certain side reactions and unpredictable risks of pazufloxacin in clinical use cases, and can be used for promoting active exploration of medicament improvement and the like of pazufloxacin.
Description
Technical field
The present invention relates to a kind of quinolone compounds and its preparation method and application.
Background technology
The English Pazufloxacin by name of Pazufloxacin, the chemistry fluoro-10-of (S)-9-(amino cyclopropyl)-3-methyl-2 by name, 3-dihydro-7-oxo-7H-pyrido [1,2,3-de] [Isosorbide-5-Nitrae] benzoxazine-6 carboxylic acid).Molecular structural formula is as follows:
Pazufloxacin is by Japan folic hill chemical industry Co., Ltd. and Mitsubishi Pharmaceutical Co., Ltd joint development, the Comprecin going on the market in Japan first in April, 2002, can act on topoisomerase and DNA gyrase simultaneously, copying of anti-bacteria DNA and bring into play anti-microbial effect, its antibacterial wide spectrum, intravenously administrable Plasma Concentration is high, toxicity to central nervous system is less, rapid-action, the activity in vivo of Dui Jin Portugal bacterium is better than Levofloxacin, norfloxicin, Ciprofloxacin, Ofloxacine USP 23 etc., particularly various resistance Staphylococcus are had to good activity.
The main component that Pazufloxacin is applied is clinically the mesylate of Pazufloxacin, be T-3762 (pazufloxacin mesylate), chemical name: the fluoro-10-of (S)-9-(1-amino-1-cyclopropyl)-3-methyl-7-oxygen-2,3-dihydro-7H-pyridine [1,2,3-de] [Isosorbide-5-Nitrae] benzoxazine-6-carboxylic acid mesylate, structural formula is as follows:
Pazufloxacin may cause that Body adverse reaction comprises Digestive tract, neural system, cardiovascular systems, blood system, urinary system, skin and appendicle official rank thereof; According to correlative study, show, in 1624 routine patients, there is altogether ADR158 example time, ADR incidence is 9.73% (158/1624), what generation number of cases was the highest is Digestive tract (comprising dysfunction of liver 15 examples) 77 examples (48.73%), secondly be cardiovascular systems (21.52%) and neural system (20.89%), it is nausea and vomiting (53 examples that the rank forefront I clinical manifestation of 5 of number of cases occurs, 33.54%), phlebitis (31 examples, 19.62%), dizzy (23 examples, 14.56%), transaminase rising (14 examples, 8.86%), fash (8 examples, 5.06%).There is not phototoxicity, cardiac toxic and tendon pathology.
Therefore, study issuable impurity in its technological process and in drug stock control process and there is very important Research Significance.
Summary of the invention
The object of the invention is provides a kind of quinolone compounds in order to solve the pathology toxicological study of research Pazufloxacin drug side effect.
The preparation method and application of the quinolone compounds that two of object of the present invention is to provide above-mentioned.
Technical scheme of the present invention
A quinolone compounds, its structural formula is as follows:
。
The synthetic method of above-mentioned a kind of quinolone compounds, concrete steps are as follows:
In solvent 1, by (S)-9, the fluoro-3-of 10-bis-methyl-2,3-dihydro-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid, ethyl ester and NaCN control temperature and are 0 ℃ and react 0.5h, then be warming up to gradually 40-90 ℃ and carry out cyanogen glycosylation reaction 10-16h, the reacting liquid filtering of gained, the filter cake of gained adds water making beating, and with water wash three times, again filter, the filter cake control temperature obtaining is 55-65 ℃ and is dried, obtains quinolone compounds;
(S)-9 that above-mentioned cyanogenation is used, the fluoro-3-of 10-bis-methyl-2,3-dihydro-7-oxo-7H-pyrido [1,2,3-de] [1,4] amount of benzoxazine-6-carboxylic acid, ethyl ester, NaCN and solvent 1, by (S)-9, the fluoro-3-of 10-bis-methyl-2,3-dihydro-7-oxo-7H-pyrido [1,2,3-de] [Isosorbide-5-Nitrae] benzoxazine-6-carboxylic acid, ethyl ester: NaCN: the ratio that solvent 1 is 1mol:2mol:3-3.1L is calculated;
Described solvent 1 is DMF (hereinafter to be referred as DMF), N,N-dimethylacetamide (hereinafter to be referred as DMAC), methane amide or N-Methyl pyrrolidone (hereinafter to be referred as NMP);
The quinolone compounds of above-mentioned gained, can be hydrolyzed and be obtained the fluoro-10-cyano group-3-of (S)-9-methyl-2, the Pazufloxacin impurity of 3-dihydro-7-oxo-7H-pyrido [1,2,3-de] [Isosorbide-5-Nitrae] benzoxazine-6-carboxylic acid, and its structural formula is as follows:
；
Above-mentioned quinolone compounds is hydrolyzed and obtains the fluoro-10-cyano group-3-of (S)-9-methyl-2, the Pazufloxacin impurity of 3-dihydro-7-oxo-7H-pyrido [1,2,3-de] [Isosorbide-5-Nitrae] benzoxazine-6-carboxylic acid, and concrete steps are as follows:
In solvent 2, by quinolone compounds, be the fluoro-10-cyano group-3-of (S)-9-methyl-2, 3-dihydro-7-oxo-7H-pyrido [1, 2, 3-de] [1, 4] benzoxazine-6-carboxylic acid, ethyl ester, under the effect of lithium hydroxide, controlling temperature is the 20-40 ℃ of reaction 2-600min that is hydrolyzed, or under salt of wormwood effect, control temperature be 65-70 ℃ be hydrolyzed reaction 60min, or under the effect of sodium bicarbonate, control temperature be 55-60 ℃ be hydrolyzed reaction 2-3h, the reaction solution of gained carries out after cancellation with hydrochloric acid, being cooled to 0-20 ℃ of stirring spends the night, then filter, the filter cake of gained is pulled an oar with methyl alcohol, filter, it is 30-40 ℃ of oven dry that gained filter cake is controlled temperature, the final Pazufloxacin impurity that obtains,
Said hydrolyzed is reacted the amount of quinolone compounds, solvent 2 and lithium hydroxide used, in quinolone compounds: solvent 2: the ratio that lithium hydroxide is 1mol:22.5-23.5L:1-6mol is calculated;
The amount of quinolone compounds used, solvent 2 and salt of wormwood, in quinolone compounds: solvent 2: the ratio that salt of wormwood is 1mol:19L:1.44mol is calculated;
The amount of quinolone compounds used, solvent 2 and sodium bicarbonate, in quinolone compounds: solvent 2: the ratio that sodium bicarbonate is 1mol:22.8L:1.94mol is calculated;
Above-mentioned solvent 2 is the mixed solvent of one or more compositions in DMF (hereinafter to be referred as DMF), N-Methyl pyrrolidone (hereinafter to be referred as NMP), methylene dichloride, alcoholic solvent, tetrahydrofuran (THF) (hereinafter to be referred as THF).
The fluoro-10-cyano group-3-of above-mentioned (S)-9-methyl-2, the Pazufloxacin impurity of 3-dihydro-7-oxo-7H-pyrido [1,2,3-de] [Isosorbide-5-Nitrae] benzoxazine-6-carboxylic acid, can be used for studying the pathology toxicological study of Pazufloxacin drug side effect.
Contribute to explain some side reactions and the Unpredictability risk that in the clinical use case of Pazufloxacin, occur, and and then promote the enthusiasm such as medicine improvement of Pazufloxacin to explore.
Beneficial effect of the present invention
A kind of quinolone compounds provided by the invention, it can obtain by hydrolysis the fluoro-10-cyano group-3-of (S)-9-methyl-2,3-dihydro-7-oxo-7H-pyrido [1,2,3-de] [1,4] the Pazufloxacin impurity of benzoxazine-6-carboxylic acid, can be used for studying the pathology toxicological study of Pazufloxacin drug side effect.This quinolone compounds also can the synthetic intermediate of drug application simultaneously.
Accompanying drawing explanation
The nucleus magnetic hydrogen spectrum spectrogram of the quinolone compounds of Fig. 1, embodiment 1 gained;
The nucleus magnetic hydrogen spectrum spectrogram of the impurity of the Pazufloxacin of Fig. 2, embodiment 2 gained.
concrete case study on implementation
Below by specific embodiment, also by reference to the accompanying drawings the present invention is further set forth, but do not limit the present invention.
In various embodiments of the present invention, raw material used or the specification of reagent and the information of manufacturer are as follows, if no special instructions, are commercially available:
DMF, commercially available AR level;
Ethanol, commercially available 95%, AR level.
embodiment 1
A quinolone compounds, its structural formula is as follows:
。
The synthetic method of above-mentioned a kind of quinolone compounds, specifically comprises the steps:
Thermometer is being housed, in the 100mL there-necked flask of reflux condensing tube and vacuum stopper, add 50mL DMF solvent, (5g, 16.2mmol) (S)-9, the fluoro-3-of 10-bis-methyl-2, 3-dihydro-7-oxo-7H-pyrido [1, 2, 3-de] [1, 4] benzoxazine-6-carboxylic acid, ethyl ester, controlling temperature is 0 ℃ of stirring and dissolving, obtain flaxen solution, then be warming up to 5 ℃, add (1.6g, 32.4mmol) NaCN solid stirs, then controlling temperature is 0 ℃ of reaction 0.5h, then be warming up to gradually 70-80 ℃ and react 10h, obtain being the reaction solution of safran clarification shape,
By the reacting liquid filtering of above-mentioned gained, the filter cake of gained adds water 5mL making beating, and with water wash three times, again filters, and the filter cake control temperature obtaining is 55-65 ℃ and is dried, and obtain 3.1g solid, yield 60.8%, identifies that through HPLC its purity is 99.1%;
(S)-9 that above-mentioned cyanogenation is used, the fluoro-3-of 10-bis-methyl-2,3-dihydro-7-oxo-7H-pyrido [1,2,3-de] [1,4] amount of benzoxazine-6-carboxylic acid, ethyl ester, NaCN and DMF, by (S)-9, the fluoro-3-of 10-bis-methyl-2,3-dihydro-7-oxo-7H-pyrido [1,2,3-de] [Isosorbide-5-Nitrae] benzoxazine-6-carboxylic acid, ethyl ester: the ratio that NaCN:DMF is 1mol:2mol:3.1L is calculated;
Adopt Avance 500MHz nuclear magnetic resonance spectrometer, Dionex MSOPlus mass spectrograph to measure the solid of above-mentioned gained, the nucleus magnetic hydrogen spectrum of gained, mass-spectrometric data result are as follows:
1HNMR?(500?MHz,?DMSO?-?d
6)?δ?8.75?(s,?1H),?7.59?(d,?J?=?9.6?Hz,?1H),?4.95?-?4.80?(m,?1H),?4.73?(dd,?J?=?9.8,?6.2?Hz,?1H),?4.58?(d,?J?=?11.3?Hz,?1H),?4.32?-?4.18?(m,?2H),?1.51?-?1.39?(m,?3H),?1.34?-?1.26?(m,?3H).?ESI-MS(m/z):?316.9?(M+1)
+.
Further, its nucleus magnetic hydrogen spectrum spectrogram as shown in Figure 1;
From nucleus magnetic hydrogen spectrum data, mass-spectrometric data and the nucleus magnetic hydrogen spectrum spectrogram of above-mentioned gained, can draw, the solid of above-mentioned gained is (S)-9, the fluoro-3-of 10-bis-methyl-2,3-dihydro-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid, ethyl ester, its structural formula is as follows:
。
application Example 1
Utilize the structural formula of embodiment 1 gained as follows:
quinolone compounds be hydrolyzed and obtain the following a kind of Pazufloxacin impurity of structural formula:
。
The hydrolytic process of above-mentioned quinolone compounds, specifically comprises following steps:
In 1000 milliliters of there-necked flasks of thermometer, dropping funnel and vacuum stopper are housed, add successively 730mL nmp solvent, the quinolone compounds of (10g, 31.6mmol) embodiment 1 gained, magnetic agitation, be heated to 50-80 ℃, system is yellow clarification, starts cooling, adds 60mL LiOH saturated aqueous solution (amounting to into lithium hydroxide solid is 189.6mmol), system is red-purple clarification shape, and controlling temperature is that the 20-40 ℃ of reaction 2-20min that is hydrolyzed obtains reaction solution;
The reaction solution of above-mentioned gained is carried out after cancellation with aqueous hydrochloric acid and 8-10mL concentrated hydrochloric acid that the concentration of 300mL is 2mol/L, add ice block cooling, with ice-water bath cooling, stirring is spent the night simultaneously, then filter, 20mL methyl alcohol making beating for the filter cake of gained, filters the filter cake of gained, controlling temperature is 30-40 ℃ of oven dry, obtain solid 4.9g, yield 54.9%, HPLC shows that purity is 98.1%;
Said hydrolyzed is reacted the amount of quinolone compounds, NMP and lithium hydroxide used, in quinolone compounds: NMP: the ratio that lithium hydroxide is 1mol:23.1L:6mol is calculated.
Adopt Avance 500MHz nuclear magnetic resonance spectrometer, Dionex MSOPlus mass spectrograph to measure the solid of above-mentioned gained, the nucleus magnetic hydrogen spectrum of gained, mass-spectrometric data result are as follows:
1H?NMR?(500?MHz,?DMSO?-?d
6)?δ?11.90?(s,?1H),?10.10?(s,?1H),?8.25?(s,?1H),?5.02?(d,?J?=?5.8?Hz,?1H),?4.86?-?4.61?(m,?1H),?4.39?(d,?J?=?10.8Hz,?1H),?1.32?(d,?J?=6.4Hz,?3H).?ESI-MS(m/z):?288.9?(M+1)
+.
Further, its nucleus magnetic hydrogen spectrum spectrogram as shown in Figure 2;
From nucleus magnetic hydrogen spectrum data, mass-spectrometric data and the nucleus magnetic hydrogen spectrum spectrogram of above-mentioned gained, can draw, the solid of above-mentioned gained is the fluoro-10-cyano group-3-of (S)-9-methyl-2,3-dihydro-7-oxo-7H-pyrido [1,2,3-de] [Isosorbide-5-Nitrae] benzoxazine-6-carboxylic acid, its structural formula is as follows:
。
embodiment 2
A quinolone compounds, its structural formula is as follows:
。
The synthetic method of above-mentioned a kind of quinolone compounds, specifically comprises the steps:
In the 100mL there-necked flask of thermometer, reflux condensing tube and vacuum stopper is housed, add 50mL DMF solvent, (5g, 16.2mmol) (S)-9, the fluoro-3-of 10-bis-methyl-2,3-dihydro-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid, ethyl ester, controlling temperature is 0 ℃ of stirring and dissolving, obtains flaxen solution, then be warming up to 5 ℃, add (1.6g, 32.4mmol) NaCN solid to stir, then controlling temperature is 0 ℃ of reaction 0.5h, then be warming up to gradually 40-50 ℃ and react 16h, obtain being the reaction solution of safran clarification shape;
By the reacting liquid filtering of above-mentioned gained, the filter cake of gained adds water 5mL making beating, and with water wash three times, again filters, and the filter cake control temperature obtaining is 55-65 ℃ and is dried, and obtain 2.59g solid, yield 50.7%, identifies that through HPLC its purity is 99.3%;
(S)-9 that above-mentioned cyanogenation is used, the fluoro-3-of 10-bis-methyl-2,3-dihydro-7-oxo-7H-pyrido [1,2,3-de] [1,4] amount of benzoxazine-6-carboxylic acid, ethyl ester, NaCN and DMF, by (S)-9, the fluoro-3-of 10-bis-methyl-2,3-dihydro-7-oxo-7H-pyrido [1,2,3-de] [Isosorbide-5-Nitrae] benzoxazine-6-carboxylic acid, ethyl ester: the ratio that NaCN:DMF is 1mol:2mol:3.1L is calculated.
The solid of above-mentioned gained is measured by nucleus magnetic hydrogen spectrum data, mass-spectrometric data and nucleus magnetic hydrogen spectrum spectrogram, result shows that the solid of above-mentioned gained is (S)-9, the fluoro-3-of 10-bis-methyl-2,3-dihydro-7-oxo-7H-pyrido [1,2,3-de] [Isosorbide-5-Nitrae] benzoxazine-6-carboxylic acid, ethyl ester, its structural formula is as follows:
。
application Example 2
Utilize the structural formula of embodiment 2 gained as follows:
quinolone compounds be hydrolyzed and obtain the following a kind of Pazufloxacin impurity of structural formula:
。
The hydrolytic process of above-mentioned quinolone compounds, specifically comprises following steps:
In 100 milliliters of there-necked flasks of thermometer, dropping funnel and vacuum stopper are housed, add successively 75mL nmp solvent, the quinolone compounds of (1g, 3.2mmol) embodiment 2 gained, magnetic agitation, be heated to 50-80 ℃, system is yellow clarification, starts cooling, adds 1.1mL LiOH saturated aqueous solution (amounting to into lithium hydroxide solid is 3.2mmol), system is red-purple clarification shape, and controlling temperature is that the 20-40 ℃ of reaction 60min that is hydrolyzed obtains reaction solution;
The reaction solution of above-mentioned gained is carried out after cancellation with aqueous hydrochloric acid and 8-10mL concentrated hydrochloric acid that the concentration of 300mL is 2mol/L, add ice block cooling, with ice-water bath cooling, stirring is spent the night, and then filters simultaneously, 20mL methyl alcohol making beating for the filter cake of gained, filter, the filter cake of gained, controlling temperature is 30-40 ℃ of oven dry, obtain solid 0.3g, yield 31.6%.HPLC shows that purity is 96.5%;
Said hydrolyzed is reacted the amount of quinolone compounds, NMP and lithium hydroxide used, in quinolone compounds: NMP: the ratio that lithium hydroxide is 1mol:23.4L:1mol is calculated.
The solid of above-mentioned gained is measured by nucleus magnetic hydrogen spectrum data, mass-spectrometric data and nucleus magnetic hydrogen spectrum spectrogram, result shows, the solid of above-mentioned gained is the fluoro-10-cyano group-3-of (S)-9-methyl-2,3-dihydro-7-oxo-7H-pyrido [1,2,3-de] [Isosorbide-5-Nitrae] benzoxazine-6-carboxylic acid, its structural formula is as follows:
。
embodiment 3
A quinolone compounds, its structural formula is as follows:
。
The synthetic method of above-mentioned a kind of quinolone compounds, specifically comprises the steps:
In the 100mL there-necked flask of thermometer, reflux condensing tube and vacuum stopper is housed, add 50mL DMF solvent, (5g, 16.2mmol) (S)-9, the fluoro-3-of 10-bis-methyl-2,3-dihydro-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid, ethyl ester, controlling temperature is 0 ℃ of stirring and dissolving, obtains flaxen solution, then be warming up to 5 ℃, add (1.6g, 32.4mmol) NaCN solid to stir, then controlling temperature is 0 ℃ of reaction 0.5h, then be warming up to gradually 50-60 ℃ and react 13h, obtain being the reaction solution of safran clarification shape;
By the reacting liquid filtering of above-mentioned gained, the filter cake of gained adds water 5mL making beating, and with water wash three times, again filters, and the filter cake control temperature obtaining is 55-65 ℃ and is dried, obtains solid 2.8g, yield 54.8%.Through HPLC, identify that its purity is 99.0%;
(S)-9 that above-mentioned cyanogenation is used, the fluoro-3-of 10-bis-methyl-2,3-dihydro-7-oxo-7H-pyrido [1,2,3-de] [1,4] amount of benzoxazine-6-carboxylic acid, ethyl ester, NaCN and solvent DMF, by (S)-9, the fluoro-3-of 10-bis-methyl-2,3-dihydro-7-oxo-7H-pyrido [1,2,3-de] [Isosorbide-5-Nitrae] benzoxazine-6-carboxylic acid, ethyl ester: the ratio that NaCN:DMF is 1mol:2mol:3.1L is calculated.
The solid of above-mentioned gained is measured by nucleus magnetic hydrogen spectrum data, mass-spectrometric data and nucleus magnetic hydrogen spectrum spectrogram, result shows that the solid of above-mentioned gained is (S)-9, the fluoro-3-of 10-bis-methyl-2,3-dihydro-7-oxo-7H-pyrido [1,2,3-de] [Isosorbide-5-Nitrae] benzoxazine-6-carboxylic acid, ethyl ester, its structural formula is as follows:
。
application Example 3
Utilize the structural formula of embodiment 3 gained as follows:
quinolone compounds be hydrolyzed and obtain the following a kind of Pazufloxacin impurity of structural formula:
。
The hydrolytic process of above-mentioned quinolone compounds, specifically comprises following steps:
In 100 milliliters of there-necked flasks of thermometer, dropping funnel and vacuum stopper are housed, add successively the mixed solvent being formed by 60mL ethanol and 12mLTHF, the quinolone compounds of (1g, 3.2mmol) embodiment 3 gained, magnetic agitation, it is yellow muddy that system is, 0 ℃ of temperature control, slowly drips 1.1mL LiOH saturated aqueous solution (amounting to into lithium hydroxide solid is 3.2mmol), and system is red-purple clarification shape, controlling temperature is the 20-40 ℃ of reaction 60min that is hydrolyzed, and obtains reaction solution;
The reaction solution of above-mentioned gained is carried out after cancellation with aqueous hydrochloric acid and 8-10mL concentrated hydrochloric acid that the concentration of 300mL is 2mol/L, add ice block cooling, with ice-water bath cooling, stirring is spent the night, and then filters simultaneously, 20mL methyl alcohol making beating for the filter cake of gained, filter, the filter cake of gained, controlling temperature is 30-40 ℃ of oven dry, obtain faint yellow solid 0.3g, yield 32.0%.HPLC shows that purity is 96.5%;
Said hydrolyzed is reacted the amount of quinolone compounds used, the mixed solvent being comprised of ethanol and THF and lithium hydroxide, in quinolone compounds: the mixed solvent being comprised of ethanol and THF: the ratio that lithium hydroxide is 1mol:22.5L:1mol is calculated;
In the mixed solvent that ethanol and THF form, the volume ratio of ethanol: THF is 5:1.
The solid of above-mentioned gained is measured by nucleus magnetic hydrogen spectrum data, mass-spectrometric data and nucleus magnetic hydrogen spectrum spectrogram, result shows, the solid of above-mentioned gained is the fluoro-10-cyano group-3-of (S)-9-methyl-2,3-dihydro-7-oxo-7H-pyrido [1,2,3-de] [Isosorbide-5-Nitrae] benzoxazine-6-carboxylic acid, its structural formula is as follows:
。
embodiment 4
A quinolone compounds, its structural formula is as follows:
。
The synthetic method of above-mentioned a kind of quinolone compounds, specifically comprises the steps:
Thermometer is being housed, in the 100mL there-necked flask of reflux condensing tube and vacuum stopper, add 50mL formamide solvent, (5g, 16.2mmol) (S)-9, the fluoro-3-of 10-bis-methyl-2, 3-dihydro-7-oxo-7H-pyrido [1, 2, 3-de] [1, 4] benzoxazine-6-carboxylic acid, ethyl ester, controlling temperature is 0 ℃ of stirring and dissolving, obtain flaxen solution, then be warming up to 5 ℃, add (1.6g, 32.4mmol) NaCN solid stirs, then controlling temperature is 0 ℃ of reaction 0.5h, then be warming up to gradually 60-70 ℃ and react 10h, obtain being the reaction solution of safran clarification shape,
By the reacting liquid filtering of above-mentioned gained, the filter cake of gained adds water 5mL making beating, and with water wash three times, again filters, and the filter cake control temperature obtaining is 55-65 ℃ and is dried, and obtain solid 2.88g, yield 56.3%, identifies that through HPLC its purity is 98.9%;
(S)-9 that above-mentioned cyanogenation is used, the fluoro-3-of 10-bis-methyl-2,3-dihydro-7-oxo-7H-pyrido [1,2,3-de] [1,4] amount of benzoxazine-6-carboxylic acid, ethyl ester, NaCN and methane amide, by (S)-9, the fluoro-3-of 10-bis-methyl-2,3-dihydro-7-oxo-7H-pyrido [1,2,3-de] [Isosorbide-5-Nitrae] benzoxazine-6-carboxylic acid, ethyl ester: NaCN: the ratio that methane amide is 1mol:2mol:3.1L is calculated.
The solid of above-mentioned gained is measured by nucleus magnetic hydrogen spectrum data, mass-spectrometric data and nucleus magnetic hydrogen spectrum spectrogram, result shows that the solid of above-mentioned gained is (S)-9, the fluoro-3-of 10-bis-methyl-2,3-dihydro-7-oxo-7H-pyrido [1,2,3-de] [Isosorbide-5-Nitrae] benzoxazine-6-carboxylic acid, ethyl ester, its structural formula is as follows:
。
application Example 4
Utilize the structural formula of embodiment 4 gained as follows:
quinolone compounds be hydrolyzed and obtain the following a kind of Pazufloxacin impurity of structural formula:
。
The hydrolytic process of above-mentioned quinolone compounds, specifically comprises following steps:
In 100 milliliters of there-necked flasks of thermometer, dropping funnel and vacuum stopper are housed, add successively the mixed solvent being formed by 30mL methylene dichloride and 30mL methyl alcohol, (1g, 3.2mmol) the quinolone compounds of embodiment 4 gained, magnetic agitation, it is yellow muddy that system is, slowly drip salt of wormwood (3.2mL, 1N) (amounting to into potash solid is 3.2mmol), is warming up to 55-60 ℃ of stirring reaction 1h, and system is not clarified; Be warming up to 60-65 ℃ of stirring reaction 3h, solution does not become clarification yet; Add salt of wormwood (0.2g) (amounting to into potash solid is 1.4mmol), be warming up to 65-70 ℃, solution clarification, stirring reaction 1h, obtains reaction solution;
The reaction solution of above-mentioned gained is carried out after cancellation with aqueous hydrochloric acid and 8-10mL concentrated hydrochloric acid that the concentration of 300mL is 2mol/L, add ice block cooling, with ice-water bath cooling, stirring is spent the night, and then filters simultaneously, 20mL methyl alcohol making beating for the filter cake of gained, filter, the filter cake of gained, controlling temperature is 30-40 ℃ of oven dry, obtain solid 0.2g, yield 19.8%.HPLC shows that purity is 91.5%;
Said hydrolyzed is reacted the amount of quinolone compounds used, the mixed solvent being comprised of methylene dichloride and methyl alcohol and salt of wormwood, in quinolone compounds: the mixed solvent being comprised of methylene dichloride and methyl alcohol: the ratio that salt of wormwood is 1mol:19L:1.44mol is calculated;
In the mixed solvent that described methylene dichloride and methyl alcohol form, methylene dichloride: the volume ratio of methyl alcohol is 1:1.
The solid of above-mentioned gained is measured by nucleus magnetic hydrogen spectrum data, mass-spectrometric data and nucleus magnetic hydrogen spectrum spectrogram, and result shows, the solid of above-mentioned gained, and its structural formula is as follows:
, be the fluoro-10-cyano group-3-of (S)-9-methyl-2,3-dihydro-7-oxo-7H-pyrido [1,2,3-de] [Isosorbide-5-Nitrae] benzoxazine-6-carboxylic acid.
embodiment 5
A quinolone compounds, its structural formula is as follows:
。
The synthetic method of above-mentioned a kind of quinolone compounds, specifically comprises the steps:
Thermometer is being housed, in the 100mL there-necked flask of reflux condensing tube and vacuum stopper, add 50mL nmp solvent, (5g, 16.2mmol) (S)-9, the fluoro-3-of 10-bis-methyl-2, 3-dihydro-7-oxo-7H-pyrido [1, 2, 3-de] [1, 4] benzoxazine-6-carboxylic acid, ethyl ester, controlling temperature is 0 ℃ of stirring and dissolving, obtain flaxen solution, then be warming up to 5 ℃, add (1.6g, 32.4mmol) NaCN solid stirs, then controlling temperature is 0 ℃ of reaction 0.5h, then be warming up to gradually 80-90 ℃ and react 10h, obtain the reaction solution that reaction solution obtains being safran clarification shape,
By the reacting liquid filtering of above-mentioned gained, the filter cake of gained adds water 5mL making beating, and with water wash three times, again filters, and the filter cake control temperature obtaining is 55-65 ℃ and is dried, and obtain solid 3.03g, yield 59.0%, identifies that through HPLC its purity is 99.2%;
(S)-9 that above-mentioned cyanogenation is used, the fluoro-3-of 10-bis-methyl-2,3-dihydro-7-oxo-7H-pyrido [1,2,3-de] [1,4] amount of benzoxazine-6-carboxylic acid, ethyl ester, NaCN and NMP, by (S)-9, the fluoro-3-of 10-bis-methyl-2,3-dihydro-7-oxo-7H-pyrido [1,2,3-de] [Isosorbide-5-Nitrae] benzoxazine-6-carboxylic acid, ethyl ester: the ratio that NaCN:NMP is 1mol:2mol:3.1L is calculated.
The solid of above-mentioned gained is measured by nucleus magnetic hydrogen spectrum data, mass-spectrometric data and nucleus magnetic hydrogen spectrum spectrogram, result shows that the solid of above-mentioned gained is (S)-9, the fluoro-3-of 10-bis-methyl-2,3-dihydro-7-oxo-7H-pyrido [1,2,3-de] [Isosorbide-5-Nitrae] benzoxazine-6-carboxylic acid, ethyl ester, its structural formula is as follows:
。
application Example 5
Utilize the structural formula of embodiment 5 gained as follows:
quinolone compounds be hydrolyzed and obtain the following a kind of Pazufloxacin impurity of structural formula:
。
The hydrolytic process of above-mentioned quinolone compounds, specifically comprises following steps:
In 100 milliliters of there-necked flasks of thermometer, dropping funnel and vacuum stopper are housed, add successively the mixed solvent being formed by 55mL methylene dichloride and 18mL methyl alcohol, (1g, 3.2mmol) the quinolone compounds of embodiment 5 gained, magnetic agitation, it is yellow muddy that system is, slowly drip sodium bicarbonate (3.2mL, 1mol/L) (amounting to into sodium bicarbonate solid is 3.2mmol), is warming up to 40-45 ℃ of stirring reaction 14h, and system is not clarified; Add sodium bicarbonate (3mL, 1mol/L) (amounting to into sodium bicarbonate solid is 3mmol), be warming up to 55-60 ℃, solution clarification, stirring reaction 2-3h, obtains reaction solution;
The reaction solution of above-mentioned gained is carried out after cancellation with aqueous hydrochloric acid and 8-10mL concentrated hydrochloric acid that the concentration of 300mL is 2mol/L, add ice block cooling, with ice-water bath cooling, stirring is spent the night simultaneously, then filter, 20mL methyl alcohol making beating for the filter cake of gained, filters the filter cake of gained, controlling temperature is 30-40 ℃ of oven dry, obtain solid 0.2g, yield 20.2%, HPLC shows that purity is 85.5%;
Said hydrolyzed is reacted mixed solvent solvent that quinolone compounds used, methylene dichloride and methyl alcohol forms and the amount of sodium bicarbonate, by quinolone compounds: the mixed solvent of methylene dichloride and methyl alcohol composition: the ratio calculating that sodium bicarbonate is 1mol:22.8L:1.94mol;
In the mixed solvent that methylene dichloride and methyl alcohol form, methylene dichloride: the volume ratio of methyl alcohol is 55:18.
The solid of above-mentioned gained is measured by nucleus magnetic hydrogen spectrum data, mass-spectrometric data and nucleus magnetic hydrogen spectrum spectrogram, result shows, the solid of above-mentioned gained is the fluoro-10-cyano group-3-of (S)-9-methyl-2,3-dihydro-7-oxo-7H-pyrido [1,2,3-de] [Isosorbide-5-Nitrae] benzoxazine-6-carboxylic acid, its structural formula is as follows:
。
Above embodiment is only not used in and limits the scope of the invention for the present invention is described.In addition, after having read the content of the present invention's instruction, those skilled in the art can make various changes or modifications the present invention, and these equivalent form of values fall within the application's appended claims limited range equally.
Claims (3)
1. a quinolone compounds, is characterized in that its structural formula is as follows:
。
2. the synthetic method of a kind of quinolone compounds as claimed in claim 1, is characterized in that specifically comprising the steps;
In solvent, by (S)-9, the fluoro-3-of 10-bis-methyl-2,3-dihydro-7-oxo-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid, ethyl ester and NaCN control temperature and are 0 ℃ and react 0.5h, then be warming up to gradually 40-90 ℃ and carry out cyanogen glycosylation reaction 10-16h, the reacting liquid filtering of gained, the filter cake of gained adds water making beating, and with water wash three times, again filter, the filter cake control temperature obtaining is 55-65 ℃ and is dried, obtains quinolone compounds;
(S)-9 that above-mentioned cyanogenation is used, the fluoro-3-of 10-bis-methyl-2,3-dihydro-7-oxo-7H-pyrido [1,2,3-de] [1,4] amount of benzoxazine-6-carboxylic acid, ethyl ester, NaCN and solvent, by (S)-9, the fluoro-3-of 10-bis-methyl-2,3-dihydro-7-oxo-7H-pyrido [1,2,3-de] [Isosorbide-5-Nitrae] benzoxazine-6-carboxylic acid, ethyl ester: NaCN: the ratio that solvent is 1mol:2mol:3-3.1L is calculated;
Described solvent is DMF, N,N-dimethylacetamide, methane amide or N-Methyl pyrrolidone.
3. quinolone compounds as claimed in claim 1 obtains the fluoro-10-cyano group-3-of (S)-9-methyl-2 for hydrolysis, the Pazufloxacin impurity of 3-dihydro-7-oxo-7H-pyrido [1,2,3-de] [Isosorbide-5-Nitrae] benzoxazine-6-carboxylic acid, and its structural formula is as follows:
；
Above-mentioned quinolone compounds is hydrolyzed and obtains the fluoro-10-cyano group-3-of (S)-9-methyl-2, the Pazufloxacin impurity of 3-dihydro-7-oxo-7H-pyrido [1,2,3-de] [Isosorbide-5-Nitrae] benzoxazine-6-carboxylic acid, and concrete steps are as follows:
In solvent, by quinolone compounds, be the fluoro-10-cyano group-3-of (S)-9-methyl-2, 3-dihydro-7-oxo-7H-pyrido [1, 2, 3-de] [1, 4] benzoxazine-6-carboxylic acid, ethyl ester, under the effect of lithium hydroxide, controlling temperature is the 20-40 ℃ of reaction 2-600min that is hydrolyzed, or under salt of wormwood effect, control temperature be 65-70 ℃ be hydrolyzed reaction 60min, or under the effect of sodium bicarbonate, control temperature be 55-60 ℃ be hydrolyzed reaction 2-3h, the reaction solution of gained carries out after cancellation with hydrochloric acid, being cooled to 0-20 ℃ of stirring spends the night, then filter, the filter cake of gained is pulled an oar with methyl alcohol, filter, it is 30-40 ℃ of oven dry that gained filter cake is controlled temperature, the final Pazufloxacin impurity that obtains,
Said hydrolyzed is reacted the amount of quinolone compounds, solvent and lithium hydroxide used, in quinolone compounds: solvent: the ratio that lithium hydroxide is 1mol:22.5-23.5L:1-6mol is calculated;
The amount of quinolone compounds used, solvent and salt of wormwood, in quinolone compounds: solvent: the ratio that salt of wormwood is 1mol:19L:1.44mol is calculated;
The amount of quinolone compounds used, solvent and sodium bicarbonate, in quinolone compounds: solvent: the ratio that sodium bicarbonate is 1mol:22.8L:1.94mol is calculated;
Above-mentioned solvent is the mixed solvent of one or more compositions in DMF, N-Methyl pyrrolidone, methylene dichloride, alcoholic solvent, tetrahydrofuran (THF).
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