CN110878047A - Gatifloxacin carboxylic acid and its synthesis method - Google Patents
Gatifloxacin carboxylic acid and its synthesis method Download PDFInfo
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- CN110878047A CN110878047A CN201911247552.1A CN201911247552A CN110878047A CN 110878047 A CN110878047 A CN 110878047A CN 201911247552 A CN201911247552 A CN 201911247552A CN 110878047 A CN110878047 A CN 110878047A
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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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Abstract
The invention relates to gatifloxacin carboxylic acid and a synthesis method thereof. The synthesis method of the gatifloxacin carboxylic acid comprises the following steps: mixing gatifloxacin cyclized ester, acid and water, and then reacting for 0.5-3 h at 50-100 ℃ to obtain gatifloxacin carboxylic acid; the acid is acetic acid, phosphoric acid or a mixed solution of acetic acid and phosphoric acid. The invention abandons concentrated sulfuric acid adopted in the traditional method, and adopts acetic acid and phosphoric acid with weak acidity to carry out synthesis reaction, firstly, the defects caused by the concentrated sulfuric acid are avoided, and the carbonization side reaction of the reaction under the condition of strong acid (concentrated sulfuric acid) is avoided, so that the synthesized gatifloxacin carboxylic acid has good color and luster and crystal form. Secondly, the filtrate after the reaction can be recycled, and the gatifloxacin carboxylic acid is synthesized by the reaction with gatifloxacin cyclization ester again, wherein the cycle frequency can reach 4 times.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to gatifloxacin carboxylic acid and a synthesis method thereof.
Background
The O-demethyl gatifloxacin carboxylic acid ethyl ester is a key intermediate for synthesizing quinolone carboxylic acid derivatives or pharmaceutically acceptable salts or hydrates thereof, has the chemical name of 1-cyclopropyl-6, 7-difluoro-8-hydroxy-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester, is favorable for improving the solubility, permeability and bioavailability of medicaments, has the characteristic of good absorbability in gastrointestinal tracts, and is widely applied.
The traditional method for synthesizing the ethyl O-demethyl gatifloxacin carboxylate comprises the following steps: 1-cyclopropyl-6, 7-difluoro-8-methoxy-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester (gatifloxacin cycloester) is adopted as a raw material, gatifloxacin carboxylic acid is obtained by hydrolysis under the action of concentrated sulfuric acid, and then the gatifloxacin carboxylic acid is obtained by hydrolysis with hydrobromic acid and esterification. However, since concentrated sulfuric acid is used in the step of synthesizing gatifloxacin carboxylic acid from gatifloxacin cycloate, a large amount of strongly acidic wastewater is generated, which burdens the wastewater treatment.
Disclosure of Invention
Based on this, it is necessary to provide gatifloxacin carboxylic acid and a synthesis method thereof, aiming at the problem that a conventional synthesis method of gatifloxacin carboxylic acid generates a large amount of strongly acidic wastewater.
A synthesis method of gatifloxacin carboxylic acid comprises the following steps:
mixing gatifloxacin cyclized ester, acid and water, and then reacting for 0.5-3 h at 50-100 ℃ to obtain gatifloxacin carboxylic acid;
the acid is acetic acid, phosphoric acid or a mixed solution of acetic acid and phosphoric acid.
In one embodiment, the gatifloxacin cyclization ester is a crude gatifloxacin cyclization ester, and the mass percentage of the gatifloxacin cyclization ester in the crude gatifloxacin cyclization ester is 95-97%.
In one embodiment, the gatifloxacin cyclization ester is a crude gatifloxacin cyclization ester, and the mass percentage of the gatifloxacin cyclization ester in the crude gatifloxacin cyclization ester is 95-97%.
In one embodiment, the mass ratio of the gatifloxacin cyclization ester to the acid is 1 (1-2).
In one embodiment, the mass volume ratio of the gatifloxacin cyclization ester to the water is 1g (5-15) ml.
In one embodiment, the pH value of the mixed solution of acetic acid and phosphoric acid is 1-2.
In one embodiment, in the mixed solution of acetic acid and phosphoric acid, the mass ratio of acetic acid to phosphoric acid is (4-6): 1.
In one embodiment, in the mixed solution of acetic acid and phosphoric acid, the mass ratio of acetic acid to phosphoric acid is 4: 1.
In one embodiment, the synthesis method of gatifloxacin carboxylic acid further comprises the step of purifying the gatifloxacin carboxylic acid: and continuously reacting the reacted system at 50-100 ℃ for 1-2 h, carrying out solid-liquid separation after crystallization, and retaining the solid to obtain the purified gatifloxacin carboxylic acid.
In one embodiment, the synthesis method of gatifloxacin carboxylic acid comprises the following steps:
the gatifloxacin cyclization ester, acetic acid, phosphoric acid and water are mixed according to the mass ratio of 3:3:1:10, and then the mixture is reacted for 0.5h at the temperature of 60 ℃ to obtain gatifloxacin carboxylic acid.
The invention provides gatifloxacin carboxylic acid which is synthesized by any one of the synthesis methods of gatifloxacin carboxylic acid.
In the traditional synthesis method of gatifloxacin carboxylic acid, a large amount of strong acid (concentrated sulfuric acid) is used as a reaction raw material, and a large amount of strong acid wastewater is generated after the reaction is finished, so that the burden of wastewater treatment is increased; in addition, the use of strong acids can severely corrode equipment and piping, resulting in a significant reduction in the life of the equipment.
The synthesis method of gatifloxacin carboxylic acid of the invention abandons concentrated sulfuric acid adopted in the traditional method and adopts acetic acid and phosphoric acid with weak acidity for synthesis reaction. Firstly, the defects caused by concentrated sulfuric acid are avoided, and the carbonization side reaction of the reaction under the condition of strong acid (concentrated sulfuric acid) is avoided, so that the synthesized gatifloxacin carboxylic acid has good color and luster and crystal form. Secondly, the filtrate after the reaction can be recycled, and the gatifloxacin carboxylic acid is synthesized by the reaction with gatifloxacin cyclization ester again, wherein the cycle frequency can reach 4 times.
In addition, the crude gatifloxacin cyclization ester can be directly reacted with the acid, so that the synthesized gatifloxacin carboxylic acid has high purity and high yield, and the synthesis method is simple to operate.
Detailed Description
The present invention will be described in detail with reference to the accompanying drawings, which illustrate embodiments of the present invention. In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
In the traditional synthesis method of gatifloxacin carboxylic acid, a large amount of strong acid (concentrated sulfuric acid) is used as a reaction raw material, and a large amount of strong acid wastewater is generated after the reaction is finished, so that the burden of wastewater treatment is increased; in addition, the use of strong acids can severely corrode equipment and piping, resulting in a significant reduction in the life of the equipment.
The synthesis method of gatifloxacin carboxylic acid provided by the invention abandons concentrated sulfuric acid adopted in the traditional method, and adopts acetic acid and phosphoric acid with weak acidity to carry out synthesis reaction.
The synthesis method of gatifloxacin carboxylic acid comprises the following steps:
mixing gatifloxacin cyclized ester, acid and water, and then reacting for 0.5-3 h at 50-100 ℃ to obtain gatifloxacin carboxylic acid;
the acid is acetic acid, phosphoric acid or a mixed solution of acetic acid and phosphoric acid.
According to the invention, acetic acid and phosphoric acid with weak acidity are adopted for reaction, firstly, the defects caused by concentrated sulfuric acid are avoided, and a carbonization side reaction caused by the reaction under the condition of strong acid (concentrated sulfuric acid) is avoided, so that the synthesized gatifloxacin carboxylic acid has good color and crystal form. Secondly, the filtrate after the reaction can be recycled, and the gatifloxacin carboxylic acid is synthesized by the reaction with gatifloxacin cyclization ester again, wherein the cycle frequency can reach 4 times. When the filtrate is recycled for more than 4 times, the reaction is continued by supplementing the acid until the color of the filtrate is dark. In addition, the synthesis method is simple to operate.
In one embodiment, the gatifloxacin cycloate is a crude gatifloxacin cycloate, and the mass percentage of the gatifloxacin cycloate in the crude gatifloxacin cycloate is 95-97%.
In the actual production of ethyl O-desmethyl gatifloxacin carboxylate, gatifloxacin cycloate is generally synthesized first and then used as a raw material for the next reaction. Because the gatifloxacin cyclization ester synthesized firstly is generally a crude product (the purity is 95-97%), and a refined gatifloxacin cyclization ester product (the purity is 99.2-99.7%) is obtained after multiple purifications, the crude gatifloxacin cyclization ester product contains more impurities relative to the refined product, and the yield and the purity of the reaction are influenced. The synthesis method can directly adopt the gatifloxacin cyclization ester crude product to synthesize gatifloxacin carboxylic acid, and the synthesized gatifloxacin carboxylic acid has high purity and high yield.
In one embodiment, the mass ratio of the gatifloxacin cyclization ester to the acid is 1 (1-2). In the reaction for synthesizing the gatifloxacin carboxylic acid, the acid is used as a solvent and a catalyst, and the mass ratio can ensure the normal operation of the hydrolysis reaction.
Furthermore, the mass volume ratio of the gatifloxacin cyclization ester to water is 1g (5-15) ml.
In one embodiment, the pH of the mixture of acetic acid and phosphoric acid is 1-2.
In one embodiment, the mass ratio of acetic acid to phosphoric acid in the mixed solution of acetic acid and phosphoric acid is (4-6): 1.
Further, in the mixed solution of acetic acid and phosphoric acid, the mass ratio of acetic acid to phosphoric acid was 4: 1.
In one embodiment, the method for synthesizing gatifloxacin carboxylic acid further comprises the step of purifying gatifloxacin carboxylic acid: and continuously reacting the reacted system at 50-100 ℃ for 1-2 h, carrying out solid-liquid separation after crystallization, and retaining the solid to obtain the purified gatifloxacin carboxylic acid.
In one embodiment, the synthesis method of gatifloxacin carboxylic acid comprises the following steps: the gatifloxacin cyclization ester, acetic acid, phosphoric acid and water are mixed according to the mass ratio of 3:3:1:10, and then the mixture is reacted for 0.5h at the temperature of 60 ℃ to obtain gatifloxacin carboxylic acid. Through continuous optimization, the yield and purity of the gatifloxacin carboxylic acid synthesized by the synthesis method of gatifloxacin carboxylic acid in the embodiment are the most excellent.
The invention also provides gatifloxacin carboxylic acid synthesized by any one of the synthesis methods of gatifloxacin carboxylic acid.
The gatifloxacin carboxylic acid synthesized by the synthesis method of gatifloxacin carboxylic acid has good color and crystal form.
The following are specific examples
The gatifloxacin cyclization ester used in the following examples had a purity of 95%.
Example 1
Mixing 32.43g of gatifloxacin cyclized ester, 40g of acetic acid and 300ml of water, heating to 100 ℃, stirring for reaction for 0.5h, then carrying out suction filtration on the reaction liquid, and retaining the solid to obtain gatifloxacin carboxylic acid. The yield is 88.8 percent, and the purity is 99.2 percent. The filtrate can be recycled for 4 times.
Example 2
Mixing 32.43g of gatifloxacin cyclization ester, 40g of phosphoric acid and 300ml of water, heating to 100 ℃, stirring for reaction for 0.5h, then carrying out suction filtration on a reaction solution, and retaining a solid to obtain gatifloxacin carboxylic acid. The yield was 88.2% and the purity 98.9%. The filtrate can be recycled for 3 times.
Example 3
Mixing 32.43g of gatifloxacin cyclization ester, 40g of acetic acid, 10g of phosphoric acid and 300ml of water, heating to 60 ℃, stirring for reaction for 0.5h, then carrying out suction filtration on a reaction solution, and retaining a solid to obtain gatifloxacin carboxylic acid. The yield was 89.5%, and the purity was 99.5%. The filtrate can be recycled for 4 times.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (10)
1. A synthesis method of gatifloxacin carboxylic acid is characterized by comprising the following steps:
mixing gatifloxacin cyclized ester, acid and water, and then reacting for 0.5-3 h at 50-100 ℃ to obtain gatifloxacin carboxylic acid;
the acid is acetic acid, phosphoric acid or a mixed solution of acetic acid and phosphoric acid.
2. The method for synthesizing gatifloxacin carboxylic acid according to claim 1, wherein the gatifloxacin cycloate is a crude gatifloxacin cycloate, and the mass percentage of the gatifloxacin cycloate in the crude gatifloxacin cycloate is 95-97%.
3. The method for synthesizing gatifloxacin carboxylic acid according to claim 1, wherein the mass ratio of gatifloxacin cycloate to the acid is 1 (1-2).
4. A synthesis method of gatifloxacin carboxylic acid according to claim 3, wherein the mass/volume ratio of gatifloxacin cyclized ester to water is 1g (5-15) ml.
5. The method for synthesizing gatifloxacin carboxylic acid according to claim 1, wherein the pH of the mixed solution of acetic acid and phosphoric acid is 1 to 2.
6. A synthesis method of gatifloxacin carboxylic acid according to claim 1, wherein the mass ratio of acetic acid to phosphoric acid in the mixed solution of acetic acid and phosphoric acid is (4-6): 1.
7. The method for synthesizing gatifloxacin carboxylic acid according to claim 6, wherein the mass ratio of acetic acid to phosphoric acid in the mixed solution of acetic acid and phosphoric acid is 4: 1.
8. A method of synthesizing gatifloxacin carboxylic acid according to claim 1 further comprising the step of purifying the gatifloxacin carboxylic acid: and continuously reacting the reacted system at 50-100 ℃ for 1-2 h, carrying out solid-liquid separation after crystallization, and retaining the solid to obtain the purified gatifloxacin carboxylic acid.
9. A method of synthesizing gatifloxacin carboxylic acid according to claim 1 comprising the steps of:
the gatifloxacin cyclization ester, acetic acid, phosphoric acid and water are mixed according to the mass ratio of 3:3:1:10, and then the mixture is reacted for 0.5h at the temperature of 60 ℃ to obtain gatifloxacin carboxylic acid.
10. A gatifloxacin carboxylic acid synthesized by the method for synthesizing gatifloxacin carboxylic acid according to any one of claims 1 to 9.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030008894A1 (en) * | 2000-12-14 | 2003-01-09 | The Procter & Gamble Company | Antimicrobial quinolones, their compositions and uses |
| CN1660838A (en) * | 2004-12-30 | 2005-08-31 | 南京圣和药业有限公司 | Method for preparing and purifying laevogyrate gatifloxacin |
| CN107778308A (en) * | 2016-08-26 | 2018-03-09 | 广东东阳光药业有限公司 | Compound and preparation method thereof |
-
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- 2019-12-09 CN CN201911247552.1A patent/CN110878047A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030008894A1 (en) * | 2000-12-14 | 2003-01-09 | The Procter & Gamble Company | Antimicrobial quinolones, their compositions and uses |
| CN1660838A (en) * | 2004-12-30 | 2005-08-31 | 南京圣和药业有限公司 | Method for preparing and purifying laevogyrate gatifloxacin |
| CN107778308A (en) * | 2016-08-26 | 2018-03-09 | 广东东阳光药业有限公司 | Compound and preparation method thereof |
Non-Patent Citations (3)
| Title |
|---|
| 刘明亮，等: "5-氨基-8-甲氧基-喹诺酮类的合成及其体外抗菌作用", 《中国抗生素杂志》 * |
| 吴文良，等: "1-环丙基-6,7-二氟-1,4-二氢-8-羟基-4-氧代喹啉-3-羧酸乙酯的合成", 《中国医药工业杂志》 * |
| 王道林，等: "新一代氟喹诺酮类抗菌素——巴洛沙星的合成", 《中国药物化学杂志》 * |
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Application publication date: 20200313 |