CN113912540A - Synthesis method of 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid - Google Patents
Synthesis method of 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid Download PDFInfo
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- CN113912540A CN113912540A CN202111526971.6A CN202111526971A CN113912540A CN 113912540 A CN113912540 A CN 113912540A CN 202111526971 A CN202111526971 A CN 202111526971A CN 113912540 A CN113912540 A CN 113912540A
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- C—CHEMISTRY; METALLURGY
- 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
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Plural Heterocyclic Compounds (AREA)
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Abstract
The invention discloses a synthesis method of 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid, which comprises the step of carrying out fluorination reaction on cyclopropanecarboxylic acid and potassium fluoride under the catalysis of a phase transfer catalyst to generate the 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid, wherein the phase transfer catalyst is a quaternary ammonium salt catalyst. The invention overcomes the defects of the prior art, simplifies the synthesis process, shortens the production time, improves the yield, reduces the production cost and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of organic chemical engineering and the technical field of synthesis of pharmaceutical raw materials, and particularly relates to a synthesis method of 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid.
Background
1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid is an important intermediate for synthesizing quinolone antibacterial drugs such as ciprofloxacin, danofloxacin, besifloxacin, clinafloxacin and the like. The compound has various synthetic methods, the synthesis method of clinafloxacin intermediate 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid is introduced in Huangshan et al, China pharmaceutical industry journal 2000.31(8)338-340, the authors in the text use 2,4, 5-trifluorobenzoic acid as raw material, react with diethyl malonate after acylchlorination, and generate aroylacetic acid ethyl ester through partial hydrolysis and decarboxylation. The method comprises the following steps of converting aroylacetic acid ethyl ester and triethyl orthoformate/acetic anhydride into halogenated 2-aroyl-3-ethoxy acrylate, reacting with cyclopropylamine, cyclizing under the action of alkali, and hydrolyzing to obtain 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid, wherein the raw material 2,4, 5-trifluorobenzoic acid in the route is difficult to obtain, the first step of acyl chlorination reaction needs a large amount of thionyl chloride, so that the requirements on equipment are high, the environmental pollution is serious, and the equipment cost is increased; the second step of the reaction with diethyl malonate requires carbon tetrachloride as a solvent, and does not meet the requirement of green production; during the third step of partial hydrolysis and decarboxylation of the acyl ester, there is a risk of formation of side products, which may lead to low yields; in the fourth step, expensive triethyl orthoformate is required. The process is optimized by Chen & Re et al, Fine and specialty Chemicals 2012.20 (6)39-42, the quality and yield of the product are further improved by changing the reaction solvent of acyl chlorination and the catalyst during cyclization, but still more defects exist.
Another method for synthesizing 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid is reported in the Journal of Heterocyclic Chemistry, 24, 181 (1987). In the method, 2, 4-dinitro-5-fluorobenzoic acid is used as a raw material, and is subjected to acyl chlorination, then the raw material reacts with diethyl malonate, partial hydrolysis and decarboxylation are carried out to generate aroylacetic acid ethyl ester, the aroylacetic acid ethyl ester reacts with cyclopropylamine, and finally cyclization is carried out under the action of alkali, and hydrolysis is carried out to obtain the 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid. The route still has the problems of expensive raw materials and serious pollution, and is not suitable for industrial production.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: provides a synthesis method of 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid, overcomes the defects of the prior art, simplifies the synthesis process, shortens the production time, improves the yield, reduces the production cost, and is suitable for industrial production.
According to the invention, 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinoline carboxylic acid is prepared by fluorinating cyclopropane carboxylic acid with potassium fluoride, and due to the electron withdrawing effect of carbonyl on a benzene ring, the para-position activation of the benzene ring is easier for a fluorinating agent to attack to generate nucleophilic substitution. The reaction equation is as follows:
in order to solve the technical problems, the technical scheme of the invention is as follows:
a synthetic method of 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid comprises the following steps:
a. the cyclopropane carboxylic acid and potassium fluoride are subjected to fluorination reaction under the catalysis of a phase transfer catalyst to generate 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinoline carboxylic acid;
the phase transfer catalyst is tetradecyl trimethyl ammonium chloride, hexadecyl trimethyl ammonium chloride, octadecyl trimethyl ammonium chloride or docosyl trimethyl ammonium chloride;
b. and d, purifying the product obtained in the step a to obtain a finished product of 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinoline carboxylic acid.
Preferably, in the step a, the reaction temperature is 165-190 ℃, the stirring speed is 300-500 rmp, and the temperature is kept for 9 hours.
More preferably, in the step a, the reaction temperature is 170-185 ℃, the stirring speed is 400rmp, and the temperature is kept for 9 hours.
Preferably, the amount of the potassium fluoride added in the step a is 1.1 to 1.5 equivalents to the cyclopropanecarboxylic acid.
More preferably, the amount of potassium fluoride added in step a is 1.2 to 1.4 equivalents to cyclopropanecarboxylic acid.
Preferably, the phase transfer catalyst in step a is behenyl trimethyl ammonium chloride.
Preferably, the addition amount of the phase transfer catalyst in the step a is 2 to 4 percent of the molar amount of the cyclopropanecarboxylic acid.
More preferably, the addition amount of the phase transfer catalyst in the step a is 3% of the molar amount of the cyclopropanecarboxylic acid.
Preferably, the purification in the step b is to cool the reaction temperature to 80 ℃, add toluene with 2 times of the weight of the cyclopropane carboxylic acid, stir for 30min, filter to remove waste salt, rinse the filter cake with a proper amount of toluene, collect the filtrate, distill under reduced pressure, cool to 0 ℃ after distilling about two thirds of the liquid, filter and dry to obtain the finished product of the 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinoline carboxylic acid crystal.
Due to the adoption of the technical scheme, the invention has the beneficial effects that:
1. according to the invention, 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinoline carboxylic acid is prepared by fluorinating cyclopropanecarboxylic acid with potassium fluoride, and due to the electron withdrawing effect of carbonyl on a benzene ring, the para-position activation of the benzene ring is easier for a fluorinating agent to attack and generate nucleophilic substitution, so that the reaction is easier to carry out, the reaction condition is milder, the control is easier during production, and the production safety is ensured; the synthesis process takes cyclopropanecarboxylic acid as a raw material and can prepare 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinoline carboxylic acid through one-step fluorination reaction, thereby greatly simplifying the synthesis process, reducing the requirements on equipment, manpower, energy, fields and the like, greatly improving the yield which can reach 96 percent to the maximum (only the fluorination yield), and being more suitable for industrial mass production;
2. the method adopts the cyclopropanecarboxylic acid as the raw material, and the cyclopropanecarboxylic acid is used as an important intermediate for producing the ciprofloxacin, so that the yield is high, the synthesis process is mature, and the price is low, thereby reducing the production cost of related products;
in a word, the invention overcomes the defects in the prior art, greatly simplifies the synthesis process, is simple to operate, shortens the production time, improves the product yield, reduces the production cost, ensures the production safety, and is very suitable for industrial production.
Detailed Description
The invention is further illustrated by the following examples.
The experimental parameters which are not specified in the embodiments are all the preferable parameters in the foregoing technical solutions, and are not described in detail in the specific embodiments.
Example 1
141.00g of cyclopropanecarboxylic acid, 37.81g (1.3 equivalent) of anhydrous potassium fluoride and 60.69g (3 mol percent of cyclopropanecarboxylic acid) of docosyltrimethylammonium chloride serving as a phase transfer catalyst are added into a 1000ml four-neck flask, the mixture is stirred and heated to 170 ℃, the temperature is kept for 9h, then the mixture is cooled to 80 ℃, 282 g of methylbenzene (2 times of the mass of the cyclopropanecarboxylic acid and the volume of the cyclopropanecarboxylic acid is 323 ml) is added and stirred for 30min, waste salt is removed by filtration, a filter cake is rinsed by the methylbenzene, the filtrate is collected and distilled under reduced pressure, two thirds of the methylbenzene is distilled out and then cooled to 0 ℃, the filtrate is filtered, and the filter residue is dried to obtain 127.26g of 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxygen-3-quinolinecarboxylic acid, the purity is 99.11 percent by measurement, and the yield is 95 percent.
Example 2
The procedure of this example was as in the first example except that the reaction temperature was 165 ℃ to give 116.34g of 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid as a measured purity of 92.43% in 81% yield.
Example 3
The procedure of this example was as in the first example except that the reaction temperature was 175 ℃ to give 126.97g of 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid as a measured purity of 99.34% in 95% yield.
Example 4
The procedure of this example was as in the first example except that the reaction temperature was 180 ℃ to give 128.01g of 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid as a measured purity of 99.57% in 96% yield.
Example 5
The procedure of this example was as in the first example except that the reaction temperature was 185 ℃ to give 128.71g of 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid as a measured purity of 99.02% in 96% yield.
Example 6
The procedure of this example was as in the first example except that the reaction temperature was 190 ℃ to give 116.34g of 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid as a measured purity of 90.67% in 89% yield.
Examples 1 to 6 summary of the experiments:
from examples 1 to 6, it is known that when the temperature is in the range of 165 to 185 ℃, the purity and yield of 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid are high, fluorination is difficult to complete at low temperature, and the phase transfer catalyst is decomposed at high temperature, wherein the optimal reaction temperature is controlled to be 170 to 180 ℃.
Example 7
The procedure of this example differs from that of example one in that the amount of potassium fluoride is 31.99g (1.1 eq.) and the other steps are the same, giving 128.08g of 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid, measured as 91.22% purity in 88% yield.
Example 8
The procedure of this example differs from the one of the example in that the amount of potassium fluoride is 34.90g (1.2 eq) and the other steps are the same, giving 124.71g of 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid, measured as 99.01% pure in 93% yield.
Example 9
The procedure of this example differs from the one of the example in that the amount of potassium fluoride is 40.72g (1.4 equivalents) and the other steps are the same, giving 126.66g of 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid having a measured purity of 99.58% and a yield of 95%.
Example 10
The procedure of this example differs from the one of the example in that the amount of potassium fluoride is 43.63g (1.5 eq.) and the other steps are the same, giving 127.57g of 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid, measured as 98.87% purity in 95% yield.
Example 1 and examples 7 to 10 experimental summary:
as is clear from examples 1, 7, 8, 9 and 10, when the equivalent of potassium fluoride is 1.1, the reaction is insufficient, resulting in low yield and purity of the product, while when the equivalent of potassium fluoride is too high, excessive potassium fluoride not only increases the cost, but also affects the subsequent purification process, resulting in reduction of the product purity and yield, and therefore, the amount of potassium fluoride added is 1.2 to 1.4 equivalents, which is equivalent to that of cyclopropanecarboxylic acid, is a preferable addition amount.
Example 11
The procedure of this example differs from the one of the example in that the phase transfer catalyst used was 35.41g of decaalkyltrimethylammonium chloride (3% of the molar amount of cyclopropanecarboxylic acid), and the same procedure was followed to give 103.60g of 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid with a purity of 76.89% and a yield of 60%.
Example 12
The procedure of this example differs from that of the first example in that the phase transfer catalyst used was dodecyltrimethylammonium chloride 39.63g (3% of the molar amount of cyclopropanecarboxylic acid), and the same procedures were followed to give 119.65g of 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid having a measured purity of 81.00% and a yield of 73%.
Example 13
The procedure of this example differs from that of the first example in that the phase transfer catalyst used was 43.84g of tetradecyltrimethylammonium chloride (3% of the molar amount of cyclopropanecarboxylic acid), and the same procedures were followed to give 117.85g of 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid, which was measured to have a purity of 98.01% and a yield of 87%.
Example 14
The procedure of this example differs from that of the first example in that 48.06g of cetyltrimethylammonium chloride (3% of the molar amount of cyclopropanecarboxylic acid) was used as a phase transfer catalyst, and the same procedure was followed to give 120.78g of 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid having a purity of 98.93% and a yield of 90%.
Example 15
The procedure of this example differs from that of example one in that the phase transfer catalyst used was octadecyl trimethyl ammonium chloride 52.27g (3% of the molar amount of cyclopropanecarboxylic acid), and the other steps were the same to give 123.37g of 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid, which was measured to have a purity of 99.01% and a yield of 92%.
Example 1 and examples 11 to 15 experimental summary:
as can be seen from examples 1, 11, 12, 13, 14 and 15, the yield and purity were high when the number of alkyl groups on the phase transfer catalyst was higher than fourteen, and thus the phase transfer catalyst was selected from tetradecyltrimethylammonium chloride, hexadecyltrimethylammonium chloride, octadecyltrimethylammonium chloride and docosyltrimethylammonium chloride, with docosyltrimethylammonium chloride being the most preferred.
Example 16
The procedure of this example differs from the one in example only in that the amount of the phase transfer catalyst was 20.23g (1% of the molar amount of cyclopropanecarboxylic acid), and the other steps were carried out in the same manner to obtain 113.58g of 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid having a measured purity of 92.34% and a yield of 79%.
Example 17
The procedure of this example differs from the one of the example in that the amount of phase transfer catalyst was 40.46g (2% of the molar amount of cyclopropanecarboxylic acid), and the same procedure was followed to give 114.19g of 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid, measured as 95.34% pure in 82% yield.
Example 18
The process of this example differs from the one of the example in that the amount of the phase transfer catalyst behenyltrimethylammonium chloride was 80.92g (4% of the molar amount of cyclopropanecarboxylic acid), and the same procedure was followed to give 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid 128.17 with a measured purity of 99.44% and a yield of 96%.
Example 1 and examples 16 to 18 experimental summary:
from examples 1, 16, 17 and 18, it is understood that the yield of 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid increases with the amount of the phase transfer catalyst used, but when it exceeds 3%, the improvement in purity and yield is not significant, and the cost performance of adding an excessive amount of the phase transfer catalyst is not high, so that the amount of the phase transfer catalyst is preferably 3%.
It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Further, it should be understood that various changes or modifications of the present invention may be made by those skilled in the art after reading the teaching of the present invention, and such equivalents may fall within the scope of the present invention as defined in the appended claims.
Claims (8)
1. A synthetic method of 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid is characterized by comprising the following steps:
a. the cyclopropane carboxylic acid and potassium fluoride are subjected to fluorination reaction under the catalysis of a phase transfer catalyst to generate 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinoline carboxylic acid; the phase transfer catalyst is tetradecyl trimethyl ammonium chloride, hexadecyl trimethyl ammonium chloride, octadecyl trimethyl ammonium chloride or docosyl trimethyl ammonium chloride;
b. and d, purifying the product obtained in the step a to obtain a finished product of 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinoline carboxylic acid.
2. The method of synthesizing 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid as claimed in claim 1, wherein: in the step a, the reaction temperature is 165-190 ℃, the stirring speed is 400rmp, and the temperature is kept for 9 hours.
3. The method of synthesizing 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid as claimed in claim 2, wherein: in the step a, the reaction temperature is 170-185 ℃, the stirring speed is 400rmp, and the temperature is kept for 9 hours.
4. The method of synthesizing 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid as claimed in claim 1, wherein: the amount of potassium fluoride added in step a is 1.1 to 1.5 equivalents to cyclopropanecarboxylic acid.
5. The method of synthesizing 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid as claimed in claim 4, wherein: the amount of potassium fluoride added in step a is 1.2 to 1.4 equivalents to cyclopropanecarboxylic acid.
6. The method of synthesizing 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid as claimed in claim 1, wherein: the phase transfer catalyst in the step a is behenyl trimethyl ammonium chloride.
7. The method of synthesizing 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid as claimed in claim 1, wherein: the addition amount of the phase transfer catalyst in the step a is 2 to 4 percent of the molar weight of the cyclopropane carboxylic acid.
8. The method of synthesizing 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid as claimed in claim 1, wherein: and the purification in the step b is to cool the reaction temperature to 80 ℃, add toluene with 2 times of the weight of the cyclopropanecarboxylic acid, stir for 30min, filter to remove waste salt, rinse a filter cake with a proper amount of toluene, collect filtrate, distill under reduced pressure, cool to 0 ℃ after distilling two thirds of liquid, and dry after filtering to obtain the finished product of the 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid crystal.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN87107230A (en) * | 1986-12-03 | 1988-07-06 | 拜尔公司 | Quinoline carboxylic acid's method for making |
| CN1357530A (en) * | 2001-07-23 | 2002-07-10 | 昆山双鹤药业有限责任公司 | Process of preparing 2,3,4-trifluoro nitrobenzene using o-chloro nitrobenzene |
| CN101353297A (en) * | 2008-09-22 | 2009-01-28 | 王俊华 | Synthetic method of 4-fluorobenzaldehyde |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN87107230A (en) * | 1986-12-03 | 1988-07-06 | 拜尔公司 | Quinoline carboxylic acid's method for making |
| EP0274033A1 (en) * | 1986-12-03 | 1988-07-13 | Bayer Ag | Process for the preparation of quinolinecarboxylic acids |
| CN1357530A (en) * | 2001-07-23 | 2002-07-10 | 昆山双鹤药业有限责任公司 | Process of preparing 2,3,4-trifluoro nitrobenzene using o-chloro nitrobenzene |
| CN101353297A (en) * | 2008-09-22 | 2009-01-28 | 王俊华 | Synthetic method of 4-fluorobenzaldehyde |
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