CN110105273B - Preparation method of important intermediate of moxifloxacin - Google Patents
Preparation method of important intermediate of moxifloxacin Download PDFInfo
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- CN110105273B CN110105273B CN201910499243.7A CN201910499243A CN110105273B CN 110105273 B CN110105273 B CN 110105273B CN 201910499243 A CN201910499243 A CN 201910499243A CN 110105273 B CN110105273 B CN 110105273B
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
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Abstract
The invention discloses a preparation method of an important intermediate of moxifloxacin, which comprises the steps of filling 2, 3-pyridine dicarboxylic acid and acetic anhydride into a first reaction kettle, heating to a reaction temperature, and stirring by using a first stirring device to obtain a reaction feed liquid; pumping the reaction feed liquid into a continuous acid removal system filled with an acid scavenger at a quantitative flow rate in the reaction process, removing generated acetic acid, and then pumping into a second reaction kettle; adding benzylamine and toluene into a second reaction kettle, and stirring for reaction by using a second stirring device; after the reaction is finished, concentrating under reduced pressure to obtain an important intermediate of moxifloxacin, namely a compound 6-benzyl-5H-pyrrolo [3,4-b ] pyridine-5, 7- (6H) -dione. The conversion rate of raw materials is effectively improved, the yield of important intermediate of moxifloxacin is greatly improved, the operability of process amplification is enhanced, and the purposes of low energy consumption and simple, rapid and continuous production are realized.
Description
Technical Field
The invention relates to the technical field of moxifloxacin hydrochloride preparation, in particular to a preparation method of an important intermediate of moxifloxacin.
Background
Moxifloxacin hydrochloride is a 4 th-generation quinolone drug, is used as a broad-spectrum and efficient 8-methoxy fluoroquinolone, prevents DNA synthesis by inhibiting DNA helicase and DNA topoisomerase IV, enhances the antibacterial activity on G+ bacteria, atypical pathogens (including mycoplasma and chlamydia) and anaerobic bacteria on the basis of 3 rd generation, and relieves the development of drug resistance of the moxifloxacin hydrochloride and enables the bacterial drug resistance of the moxifloxacin to be lower.
The compound 6-benzyl-5H-pyrrolo [3,4-b ] pyridine-5, 7- (6H) -dione is an important intermediate for synthesizing moxifloxacin, and is obtained by a series of reactions of 2, 3-pyridine dicarboxylic acid.
However, acetic anhydride is subjected to alcoholysis by 2, 3-pyridine dicarboxylic acid to generate acetic acid as a byproduct, and acetic acid with a high boiling point is difficult to remove in the industrial amplification process, so that the conversion rate of raw materials is low, the yield of an important intermediate of moxifloxacin is low, the operability of process amplification is reduced, the energy consumption is increased, and the simple and rapid continuous production cannot be realized.
Disclosure of Invention
The invention aims to provide a preparation method of an important moxifloxacin intermediate, which aims to solve the technical problems that in the preparation process of the important moxifloxacin intermediate in the prior art, acetic acid with a high boiling point is difficult to remove in the industrial amplification process, so that the raw material conversion rate is low, the yield of the important moxifloxacin intermediate is low, the operability of process amplification is reduced, the energy consumption is increased, and the continuous production cannot be simply and rapidly performed.
In order to achieve the above purpose, the preparation method of the moxifloxacin important intermediate adopted by the invention comprises the following steps:
2, 3-pyridine dicarboxylic acid and acetic anhydride are put into a first reaction kettle, heated to the reaction temperature, and stirred by a first stirring device to prepare reaction feed liquid;
pumping the reaction feed liquid into a continuous acid removal system filled with an acid scavenger at a quantitative flow rate in the reaction process, removing generated acetic acid, and then pumping into a second reaction kettle;
adding benzylamine and toluene into a second reaction kettle, and stirring for reaction by using a second stirring device;
after the reaction is finished, concentrating under reduced pressure to obtain an important intermediate of moxifloxacin, namely a compound 6-benzyl-5H-pyrrolo [3,4-b ] pyridine-5, 7- (6H) -dione.
Wherein the molar ratio of the 2, 3-pyridine dicarboxylic acid to the acetic anhydride is 1:1-1:4.
Wherein the reaction temperature of the 2, 3-pyridine dicarboxylic acid and acetic anhydride in the first reaction kettle is 100-140 ℃.
The stirring rotating speed of the first stirring device is 400-450 r/min.
Wherein the reaction time of loading the 2, 3-pyridine dicarboxylic acid and the acetic anhydride into the first reaction kettle is 3-6 hours.
Wherein, the continuous acid removal system filled with acid scavenger is an acid removal column filled with acid scavenger, or a series combination of two or more acid removal columns filled with acid scavenger, or a parallel combination of two or more acid removal columns filled with acid scavenger.
Wherein the acid scavenger is one or more of sodium hydroxide, potassium hydroxide, anhydrous sodium carbonate or calcium hydroxide.
And adding benzylamine and toluene into the second reaction kettle, and carrying out stirring reaction, wherein the reaction temperature of the stirring reaction is 30-50 ℃.
Wherein the stirring rotating speed of the second stirring device is 200-300 r/min.
And adding benzylamine and toluene into the second reaction kettle, and carrying out stirring reaction for 3-5 hours.
According to the preparation method of the moxifloxacin important intermediate, 2, 3-pyridine dicarboxylic acid and acetic anhydride are filled into a first reaction kettle, the temperature is raised to the reaction temperature, and a first stirring device is used for stirring to prepare reaction feed liquid; pumping the reaction feed liquid into a continuous acid removal system filled with an acid scavenger at a quantitative flow rate in the reaction process, removing generated acetic acid, and then pumping into a second reaction kettle; adding benzylamine and toluene into a second reaction kettle, and stirring for reaction by using a second stirring device; after the reaction is finished, concentrating under reduced pressure to obtain an important intermediate of moxifloxacin, namely a compound 6-benzyl-5H-pyrrolo [3,4-b ] pyridine-5, 7- (6H) -dione.
The continuous acid removal system is utilized to remove the generated byproduct acetic acid, so that the conversion rate of raw materials is effectively improved, the yield of important intermediates of moxifloxacin is greatly improved, the operability of process amplification is enhanced, and the effects of low energy consumption and simple, rapid and continuous production are realized.
Drawings
In order to more clearly illustrate the embodiments of the invention or the technical solutions in the prior art, the drawings that are required in the embodiments or the description of the prior art will be briefly described, it being obvious that the drawings in the following description are only some embodiments of the invention, and that other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a flow chart of example 1 of a process for the preparation of an important intermediate of moxifloxacin of the present invention.
FIG. 2 is a flow chart of example 2 of a process for the preparation of an important intermediate of moxifloxacin of the present invention.
FIG. 3 is a flow chart of example 3 of a process for the preparation of an important intermediate of moxifloxacin of the present invention.
FIG. 4 is a flow chart of example 4 of a process for the preparation of an important intermediate of moxifloxacin of the present invention.
Detailed Description
Embodiments of the present invention are described in detail below, examples of which are illustrated in the accompanying drawings, wherein like or similar reference numerals refer to like or similar elements or elements having like or similar functions throughout.
The embodiments described below by referring to the drawings are illustrative and intended to explain the present invention and should not be construed as limiting the invention.
In the description of the present invention, it should be understood that the terms "length," "width," "upper," "lower," "front," "rear," "left," "right," "vertical," "horizontal," "top," "bottom," "inner," "outer," and the like indicate orientations or positional relationships based on the orientation or positional relationships shown in the drawings, merely to facilitate describing the present invention and simplify the description, and do not indicate or imply that the devices or elements referred to must have a specific orientation, be configured and operated in a specific orientation, and therefore should not be construed as limiting the present invention.
Furthermore, in the description of the present invention, the meaning of "a plurality" is two or more, unless explicitly defined otherwise.
Referring to fig. 1, embodiment 1: the qualitative and quantitative detection method for the reaction substrate and the product comprises the following steps: the mobile phase was prepared using a Kromasil C18 column (12.5 cm. Times.4.6 mm. Times.5 μm): acetonitrile water equal ratio mixed solution; UV detection wavelength: 214nm, flow rate: 1.0mL/min; the method for synthesizing the important intermediate of moxifloxacin at the column temperature of 30 ℃ comprises the following steps:
s100: 2, 3-pyridine dicarboxylic acid and acetic anhydride are filled into a first reaction kettle according to the mol ratio of 1:1, the temperature is raised to 120 ℃, and a first stirring device is used for stirring and reacting the mixture in the first reaction kettle at the rotating speed of 425r/min for 3 hours to prepare reaction feed liquid;
s200: pumping the reaction material liquid into a single-column continuous acid removal system filled with sodium hydroxide to remove generated acetic acid in the reaction process, and pumping the acetic acid into a second reaction kettle;
s300: adding benzylamine and toluene into a second reaction kettle, and stirring and reacting at the rotation speed of 250 r/min by using a second stirring device, wherein the stirring and reacting temperature is 40 ℃, and the stirring and reacting time is 3 hours;
s400: after the reaction is finished, concentrating under reduced pressure to obtain an important moxifloxacin intermediate, namely a compound 6-benzyl-5H-pyrrolo [3,4-b ] pyridine-5, 7- (6H) -dione, wherein the yield is 96.3%, and the chemical purity is 98.7%.
The method comprises the steps of loading 2, 3-pyridine dicarboxylic acid and acetic anhydride into a first reaction kettle according to a molar ratio of 1:1, heating the temperature in the first reaction kettle by using a heating device, namely a heater, and when the temperature is raised to 120 ℃, starting to react the 2, 3-pyridine dicarboxylic acid and acetic anhydride, strongly stirring a mixture in the first reaction kettle at a rotating speed of 425r/min by using a first stirring device, namely a first stirrer, stirring for 3H to obtain a reaction feed liquid, pumping the reaction feed liquid into a single-column continuous acid removal system filled with sodium hydroxide at a quantitative flow rate in the reaction process to remove generated acetic acid, pumping the reaction feed liquid into a second reaction kettle, adding benzylamine and toluene into the second reaction kettle, stirring the reaction feed liquid by using a second stirring device, namely a second stirrer at a rotating speed of 250 r/min, wherein the stirring reaction temperature is 40 ℃, the stirring reaction time is 3H, and then concentrating under reduced pressure to obtain an important moxifloxacin intermediate, namely the compound 6-benzyl-5H-pyrrolo [3,4-b ] pyridine-7, 7- (6.98%) of purity, wherein the chemical purity is 96.96%.
Referring to fig. 2, embodiment 2: the qualitative and quantitative detection method of the reaction substrate and the product is the same as that of the example 1, and the method for synthesizing the important intermediate of moxifloxacin by changing the mole ratio of the reactants and the operation parameters comprises the following steps:
s100: 2, 3-pyridine dicarboxylic acid and acetic anhydride are filled into a first reaction kettle according to the mol ratio of 1:2, the temperature is raised to 100 ℃, and a first stirring device is used for stirring and reacting the mixture in the first reaction kettle at the rotating speed of 400r/min for 6 hours to prepare a reaction feed liquid;
s200: pumping the reaction material liquid into a single-column continuous acid removal system filled with sodium hydroxide to remove generated acetic acid in the reaction process, and pumping the acetic acid into a second reaction kettle;
s300: adding benzylamine and toluene into a second reaction kettle, and stirring and reacting at the rotation speed of 200 r/min by using a second stirring device, wherein the stirring and reacting temperature is 50 ℃, and the stirring and reacting time is 1h;
s400: after the reaction is finished, concentrating under reduced pressure to obtain an important moxifloxacin intermediate, namely a compound 6-benzyl-5H-pyrrolo [3,4-b ] pyridine-5, 7- (6H) -dione, wherein the yield is 97.4%, and the chemical purity is 99.2%.
The method comprises the steps of loading 2, 3-pyridine dicarboxylic acid and acetic anhydride into a first reaction kettle according to a molar ratio of 1:1, heating the temperature in the first reaction kettle by using a heating device, namely a heater, and when the temperature is raised to 100 ℃, starting to react the 2, 3-pyridine dicarboxylic acid and the acetic anhydride, and strongly stirring a mixture in the first reaction kettle at a rotating speed of 400r/min by using a first stirring device, namely a first stirrer, wherein the stirring reaction time is 6H, so as to obtain a reaction feed liquid, pumping the reaction feed liquid into a single-column continuous acid removal system filled with sodium hydroxide at a quantitative flow rate in the reaction process to remove generated acetic acid, pumping the reaction feed liquid into a second reaction kettle, adding benzylamine and toluene into the second reaction kettle, stirring the reaction feed liquid into the second reaction kettle by using a second stirring device, namely the second stirrer, wherein the stirring reaction is carried out at a rotating speed of 200 r/min, the stirring reaction temperature is 50 ℃, the stirring reaction time is 1H, and then concentrating under reduced pressure to obtain an important moxifloxacin intermediate, namely the compound 6-benzyl-5H-pyrrolo [3,4-b ] pyridine-7-7.7% and the chemical purity of 2.97%.
Referring to fig. 3, embodiment 3: the qualitative and quantitative detection method of the reaction substrate and the product is the same as that of the example 1, and the method for synthesizing the important intermediate of moxifloxacin by changing the mole ratio of the reactants and the operation parameters comprises the following steps:
s100: 2, 3-pyridine dicarboxylic acid and acetic anhydride are filled into a first reaction kettle according to the mol ratio of 1:3, the temperature is raised to 110 ℃, and a first stirring device is used for stirring and reacting the mixture in the first reaction kettle at the rotating speed of 450r/min for 2 hours to prepare a reaction feed liquid;
s200: pumping the reaction material liquid into a single-column continuous acid removal system filled with sodium hydroxide to remove generated acetic acid in the reaction process, and pumping the acetic acid into a second reaction kettle;
s300: adding benzylamine and toluene into a second reaction kettle, and stirring and reacting at the rotation speed of 300 r/min by using a second stirring device, wherein the stirring and reacting temperature is 30 ℃, and the stirring and reacting time is 5 hours;
s400: after the reaction is finished, concentrating under reduced pressure to obtain an important moxifloxacin intermediate, namely a compound 6-benzyl-5H-pyrrolo [3,4-b ] pyridine-5, 7- (6H) -dione, wherein the yield is 96.8%, and the chemical purity is 99.1%.
The method comprises the steps of loading 2, 3-pyridine dicarboxylic acid and acetic anhydride into a first reaction kettle according to a molar ratio of 1:1, heating the temperature in the first reaction kettle by using a heating device, namely a heater, and when the temperature is raised to 110 ℃, starting to react the 2, 3-pyridine dicarboxylic acid and acetic anhydride, strongly stirring a mixture in the first reaction kettle at a rotating speed of 450r/min by using a first stirring device, namely a first stirrer, stirring for 2H to obtain a reaction feed liquid, pumping the reaction feed liquid into a single-column continuous acid removal system filled with sodium hydroxide at a quantitative flow rate in the reaction process to remove generated acetic acid, pumping the reaction feed liquid into a second reaction kettle, adding benzylamine and toluene into the second reaction kettle, stirring the reaction feed liquid by using a second stirring device, namely a second stirrer at a rotating speed of 300 r/min, wherein the stirring reaction temperature is 30 ℃, the stirring reaction time is 5H, and then concentrating under reduced pressure to obtain an important moxifloxacin intermediate, namely the compound 6-benzyl-5H-pyrrolo [3,4-b ] pyridine-7, 7- (6.99.8%) of purity is 1.96%.
Referring to fig. 4, embodiment 4: the qualitative and quantitative detection method of the reaction substrate and the product is the same as that of the example 1, and the method for synthesizing the important intermediate of moxifloxacin by changing the mole ratio of the reactants and the operation parameters comprises the following steps:
s100: 2, 3-pyridine dicarboxylic acid and acetic anhydride are filled into a first reaction kettle according to the mol ratio of 1:4, the temperature is raised to 130 ℃, and a first stirring device is used for stirring and reacting the mixture in the first reaction kettle at the rotating speed of 450r/min for 1h to prepare a reaction feed liquid;
s200: pumping the reaction material liquid into a single-column continuous acid removal system filled with sodium hydroxide to remove generated acetic acid in the reaction process, and pumping the acetic acid into a second reaction kettle;
s300: adding benzylamine and toluene into a second reaction kettle, and stirring and reacting at the rotation speed of 300 r/min by using a second stirring device, wherein the stirring and reacting temperature is 50 ℃, and the stirring and reacting time is 6 hours;
s400: after the reaction is finished, concentrating under reduced pressure to obtain an important moxifloxacin intermediate, namely a compound 6-benzyl-5H-pyrrolo [3,4-b ] pyridine-5, 7- (6H) -dione, wherein the yield is 95.2%, and the chemical purity is 98.5%.
The method comprises the steps of loading 2, 3-pyridine dicarboxylic acid and acetic anhydride into a first reaction kettle according to a molar ratio of 1:1, heating the temperature in the first reaction kettle by using a heating device, namely a heater, and when the temperature is raised to 130 ℃, starting to react the 2, 3-pyridine dicarboxylic acid and the acetic anhydride, and strongly stirring a mixture in the first reaction kettle at a rotating speed of 450r/min by using a first stirring device, namely a first stirrer, wherein the stirring reaction time is 1H, so as to obtain a reaction feed liquid, pumping the reaction feed liquid into a single-column continuous acid removal system filled with sodium hydroxide at a quantitative flow rate in the reaction process to remove generated acetic acid, pumping the reaction feed liquid into a second reaction kettle, adding benzylamine and toluene into the second reaction kettle, stirring the reaction feed liquid into the second reaction kettle by using a second stirring device, namely the second stirrer, wherein the stirring reaction is carried out at a rotating speed of 300 r/min, the stirring reaction temperature is 50 ℃, the stirring reaction time is 6H, and then concentrating under reduced pressure to obtain an important intermediate of the compound 6-benzyl-5H-pyrrolo [3,4-b ] pyridine-7.7-dione, wherein the chemical purity is 2.95%.
According to the analysis and comparison of the embodiment 1, the embodiment 2, the embodiment 3 and the embodiment 4, the reaction temperature of the 2, 3-pyridine dicarboxylic acid and the acetic anhydride in the first reaction kettle is 100 ℃, the stirring rotation speed of the first stirring device is 400r/min, the reaction time of the 2, 3-pyridine dicarboxylic acid and the acetic anhydride in the first reaction kettle is 6h, the stirring rotation speed of the second stirring device is 200 r/min, benzylamine and toluene are added into the second reaction kettle, the stirring reaction is carried out, the reaction temperature is 50 ℃, the reaction time of the stirring reaction is 1h, the conversion rate of raw materials is the highest, the yield of the important intermediate of moxifloxacin is greatly improved, the process amplification operability is enhanced, and the simple and rapid continuous production can be realized.
The above disclosure is only a preferred embodiment of the present invention, and it should be understood that the scope of the invention is not limited thereto, and those skilled in the art will appreciate that all or part of the procedures described above can be performed according to the equivalent changes of the claims, and still fall within the scope of the present invention.
Claims (8)
1. The preparation method of the important intermediate of moxifloxacin is characterized by comprising the following steps:
2, 3-pyridine dicarboxylic acid and acetic anhydride are put into a first reaction kettle, heated to the reaction temperature, and stirred by a first stirring device to prepare reaction feed liquid;
pumping the reaction feed liquid into a continuous acid removal system filled with an acid scavenger at a quantitative flow rate in the reaction process, removing generated acetic acid, and then pumping into a second reaction kettle;
adding benzylamine and toluene into a second reaction kettle, and stirring for reaction by using a second stirring device;
after the reaction is finished, concentrating under reduced pressure to obtain an important moxifloxacin intermediate, namely a compound 6-benzyl-5H-pyrrolo [3,4-b ] pyridine-5, 7- (6H) -dione;
the acid scavenger is one or more of sodium hydroxide, potassium hydroxide, anhydrous sodium carbonate or calcium hydroxide, and the continuous acid scavenger system filled with the acid scavenger is an acid scavenger column filled with the acid scavenger, or a series combination of two or more acid scavenger columns filled with the acid scavenger, or a parallel combination of two or more acid scavenger columns filled with the acid scavenger.
2. The method for preparing the moxifloxacin important intermediate as set forth in claim 1, characterized in that,
the molar ratio of the 2, 3-pyridine dicarboxylic acid to the acetic anhydride is 1:1-1:4.
3. The method for preparing the moxifloxacin important intermediate as set forth in claim 1, characterized in that,
the reaction temperature of the 2, 3-pyridine dicarboxylic acid and acetic anhydride in the first reaction kettle is 100-140 ℃.
4. The method for preparing the moxifloxacin important intermediate as set forth in claim 1, characterized in that,
the stirring rotating speed of the first stirring device is 400-450 r/min.
5. The method for preparing the moxifloxacin important intermediate as set forth in claim 1, characterized in that,
and the reaction time of loading the 2, 3-pyridine dicarboxylic acid and the acetic anhydride into the first reaction kettle is 3-6 hours.
6. The method for preparing the moxifloxacin important intermediate as set forth in claim 1, characterized in that,
and adding benzylamine and toluene into the second reaction kettle, and carrying out stirring reaction, wherein the reaction temperature of the stirring reaction is 30-50 ℃.
7. The method for preparing the moxifloxacin important intermediate as set forth in claim 1, characterized in that,
the stirring rotating speed of the second stirring device is 200-300 r/min.
8. The method for preparing the moxifloxacin important intermediate as set forth in claim 1, characterized in that,
and adding benzylamine and toluene into the second reaction kettle, and carrying out stirring reaction for 3-5 hours.
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| JP2000344769A (en) * | 1999-06-04 | 2000-12-12 | Tama Kagaku Kogyo Kk | Production of n-benzylquinolinic acid imide |
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| CN105777750A (en) * | 2016-04-13 | 2016-07-20 | 江西中德诚信科技有限公司 | Synthesis method for moxifloxacin side chain |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2000344769A (en) * | 1999-06-04 | 2000-12-12 | Tama Kagaku Kogyo Kk | Production of n-benzylquinolinic acid imide |
| WO2010131145A1 (en) * | 2009-05-12 | 2010-11-18 | Pfizer Limited | Cyclobutenedione derivatives |
| CN105777750A (en) * | 2016-04-13 | 2016-07-20 | 江西中德诚信科技有限公司 | Synthesis method for moxifloxacin side chain |
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| Title |
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| Synthesis and pharmacological activity of 3-carboxypicolinic acid amides;T. F. Odegova等;《Pharmaceutical Chemistry Journal》;20101211;第44卷;第476页左栏第1-2段 * |
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