CN109651386B - Synthetic method of oxolinic acid - Google Patents
Synthetic method of oxolinic acid Download PDFInfo
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- CN109651386B CN109651386B CN201811634218.7A CN201811634218A CN109651386B CN 109651386 B CN109651386 B CN 109651386B CN 201811634218 A CN201811634218 A CN 201811634218A CN 109651386 B CN109651386 B CN 109651386B
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- oxolinic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
Abstract
The invention relates to a synthetic method of oxolinic acid, belonging to the technical field of chemical synthesis. The synthesis method provided by the invention comprises the following steps: (1) reacting the compound I with the compound II at 120-150 ℃ to obtain a compound III; (2) cooling the mixed liquid obtained in the step (1) to 70-110 ℃, sequentially adding acetic anhydride and concentrated sulfuric acid, and heating to 120-140 ℃ for reaction; (3) and (3) after the reaction in the step (2) is finished, cooling to 80-95 ℃, and adding water for hydrolysis reaction to obtain the product. The method has the advantages of high yield, greatly reduced production cost and good product quality, and is suitable for industrial production. The specific synthetic route is as follows:
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a synthesis method of oxolinic acid.
Background
Oxoquinolic acid is also called oxocyclo-oxolinic acid, and its chemical name is 1-ethyl-6, 7-methyleneoxy-4-quinolinone-3-carboxylic acid (1-ethyl-6, 7-methyleneoxole-4-quinoline-3-carboxlicacid). Belongs to an antibacterial drug for aquaculture, and is commonly used for treating fish sarcoidosis, vibriosis, red fin disease, red spot disease, verruca, ulcer, enteritis, and the like, as well as bacterial diseases of shrimps. It is one of the ideal medicines for treating aquatic animal diseases, and has been widely used in European Union, America, south America, east Asia, southeast Asia, etc.
Through consulting the literature, a plurality of feasible process routes are found for the chemical synthesis of the oxolinic acid. In journal, "research on synthesis process of oxolinic acid", N-ethyl-3, 4- (methylenedioxy) aniline as a raw material and diethyl ethoxymethylenemalonate (EMME) were synthesized into oxolinic acid ester, which was hydrolyzed to obtain oxolinic acid with a yield of 84.9%. The method has the following disadvantages: the raw material diethyl ethoxymethylene malonate (EMME) is expensive, the reaction yield is low, the production cost is high, and the method is not suitable for industrial production.
Disclosure of Invention
The invention aims to provide a synthetic method of oxolinic acid on the basis of the prior art, which has the advantages of easily available raw materials and low cost and is suitable for synthesizing the oxolinic acid in industrial production.
The technical scheme of the invention is as follows:
a synthetic method of oxolinic acid comprises the following steps:
wherein, the compound I is N-ethyl-3, 4- (methylenedioxy) aniline; the compound II is dimethyl amino methylene diethyl malonate.
The synthesis method of the oxolinic acid provided by the invention further comprises the following steps:
(1) reacting the compound I with the compound II at 120-150 ℃ to obtain a compound III;
(2) cooling the mixed liquid obtained in the step (1) to 70-110 ℃, sequentially adding acetic anhydride and concentrated sulfuric acid, and heating to 120-140 ℃ for reaction;
(3) and (3) after the reaction in the step (2) is finished, cooling to 80-95 ℃, and adding water for hydrolysis reaction to obtain the product.
In a preferred embodiment, in step (1), the molar ratio of compound II to compound I is 1.0-2.5: 1, and more preferably 1.0-2.0: 1. The molar ratio of the compound II to the compound I is more preferably 1.1 to 1.5:1 without affecting the effect of the present invention. The molar ratio of compound II to compound I may be, for example but not limited to: 1.0:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2.0:1, 2.2:1, or 2.5: 1.
In a more preferred embodiment, in step (1), compound I and compound II are reacted at 140 ℃.
Further, the reaction time of the compound I and the compound II is 2-7 h; it is preferably 3 hours without affecting the effect of the present invention.
In a preferred embodiment, in the step (2), the molar ratio of acetic anhydride to the compound I is 1.0-2.5: 1, preferably 1.5-2.0: 1. For example, but not limited to: 1.0:1, 1.2:1, 1.5:1, 1.8:1, 2.0:1, 2.2:1 or 2.5: 1.
Further, in the step (2), the molar ratio of concentrated sulfuric acid to the compound I is 1.0-2.5: 1, preferably 1.0-1.5: 1. For example, but not limited to: 1.0:1, 1.2:1, 1.5:1, 1.8:1, 2.0:1, 2.2:1 or 2.5: 1.
In a more preferable scheme, in the step (2), the mixed solution obtained in the step (1) is cooled to 100 ℃, acetic anhydride is added, the temperature is further cooled to 80 ℃, and concentrated sulfuric acid is added.
Further, in the step (2), cooling the mixed solution obtained in the step (1) to 100 ℃, adding acetic anhydride, cooling to 80 ℃, adding concentrated sulfuric acid, heating to 130 ℃ for reaction, wherein the reaction time is 3-8 hours; it is preferably 4 hours without affecting the effect of the present invention.
Aiming at the problems in the prior art, the invention provides a synthesis method of oxolinic acid by adopting dimethyl aminomethylene diethyl malonate to replace ethoxymethylene diethyl malonate as a reaction raw material, and in a preferable scheme, the synthesis method comprises the following steps:
adding N-ethyl-3, 4- (methylenedioxy) aniline into dimethyl aminomethylene diethyl malonate, heating to 120-150 ℃, reacting for 2-7 hours, cooling to 100 ℃, adding acetic anhydride, cooling to 80 ℃, slowly adding concentrated sulfuric acid, heating to 130 ℃ after adding, reacting for 3-8 hours, cooling to 90 ℃ after the reaction is finished, adding water, performing hydrolysis reaction, cooling to room temperature after the reaction is finished, filtering, and drying to obtain oxolinic acid.
By adopting the technical scheme of the invention, the advantages are as follows:
according to the synthesis method of the oxolinic acid, dimethyl aminomethylene diethyl malonate is used as a reaction raw material instead of ethoxymethylene diethyl malonate, so that the synthesis method of the oxolinic acid is high in reaction yield, greatly reduced in production cost, good in product quality and suitable for industrial production.
Detailed Description
The synthesis method of oxolinic acid of the present invention is further illustrated by the following examples, which are not intended to limit the present invention in any way.
Example 1
Adding N-ethyl-3, 4- (methylenedioxy) aniline (compound I82.5 g,0.5mol) into dimethyl aminomethylene diethyl malonate (compound II 118g,0.55mol), heating to 140 ℃ for reaction for 3 hours, cooling to 100 ℃, adding acetic anhydride (76.5g,0.75mol), cooling to 80 ℃, slowly adding concentrated sulfuric acid (50g,0.5mol), after the addition is finished, heating to 130 ℃ for reaction for 4 hours, cooling to 90 ℃ after the reaction is finished, adding 530g of water, hydrolyzing for 3 hours, cooling to room temperature, filtering, refining, and drying to obtain the oxolinic acid.
Examples 2 to 5 refer to example 1, which is the same as example 1 except for the following table contents.
Claims (7)
1. A synthetic method of oxolinic acid is characterized by comprising the following steps:
(1) reacting the compound I with the compound II at 140 ℃ to obtain a compound III;
(2) cooling the mixed solution obtained in the step (1) to 100 ℃, adding acetic anhydride, cooling to 80 ℃, adding concentrated sulfuric acid, and heating to 130 ℃ for reaction;
(3) after the reaction in the step (2) is finished, cooling to 80-95 ℃, adding water for hydrolysis reaction to obtain the product;
wherein the content of the first and second substances,
in the step (1), the molar ratio of the compound II to the compound I is 1.1-1.5: 1;
in the step (2), the molar ratio of acetic anhydride to the compound I is 1.0-2.5: 1;
in the step (2), the molar ratio of concentrated sulfuric acid to the compound I is 1.0-2.5: 1.
2. The method for synthesizing oxolinic acid as claimed in claim 1, wherein in the step (2), the molar ratio of acetic anhydride to the compound I is 1.5-2.0: 1.
3. The method for synthesizing oxolinic acid according to claim 1, wherein in the step (2), the molar ratio of concentrated sulfuric acid to the compound I is 1.0-1.5: 1.
4. The method for synthesizing oxolinic acid as claimed in claim 1, wherein in the step (1), the reaction time of the compound I and the compound II is 2-7 h.
5. The method for synthesizing oxolinic acid according to claim 4, wherein the reaction time of the compound I and the compound II is 3 hours.
6. The method for synthesizing oxolinic acid according to claim 1, wherein in the step (2), after the acetic anhydride and the concentrated sulfuric acid are added, the reaction is carried out for 3-8 hours.
7. The method for synthesizing oxolinic acid according to claim 6, wherein the reaction time is 4 hours after adding acetic anhydride and concentrated sulfuric acid in the step (2).
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| CN201811634218.7A CN109651386B (en) | 2018-12-29 | 2018-12-29 | Synthetic method of oxolinic acid |
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| CN201811634218.7A CN109651386B (en) | 2018-12-29 | 2018-12-29 | Synthetic method of oxolinic acid |
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| CN109651386A CN109651386A (en) | 2019-04-19 |
| CN109651386B true CN109651386B (en) | 2020-08-21 |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3761482A (en) * | 1969-07-09 | 1973-09-25 | Sumitomo Chemical Co | Process and intermediates for the preparation of n-substituted 6,7-methylenedioxy-4-quinolone derivatives |
| US3917605A (en) * | 1969-07-09 | 1975-11-04 | Takenari Nakagome | Process for the preparation on N-substituted 6,7-methylenedioxy-4-quinolone derivatives |
| EP0549263A2 (en) * | 1991-12-27 | 1993-06-30 | Chemagis Ltd. | A process for the preparation of N-alkyl-3,4-dialkyloxyanilines and derivatives thereof |
| CN107108429A (en) * | 2015-12-23 | 2017-08-29 | 联邦科学与工业研究组织 | Compound |
-
2018
- 2018-12-29 CN CN201811634218.7A patent/CN109651386B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3761482A (en) * | 1969-07-09 | 1973-09-25 | Sumitomo Chemical Co | Process and intermediates for the preparation of n-substituted 6,7-methylenedioxy-4-quinolone derivatives |
| US3917605A (en) * | 1969-07-09 | 1975-11-04 | Takenari Nakagome | Process for the preparation on N-substituted 6,7-methylenedioxy-4-quinolone derivatives |
| EP0549263A2 (en) * | 1991-12-27 | 1993-06-30 | Chemagis Ltd. | A process for the preparation of N-alkyl-3,4-dialkyloxyanilines and derivatives thereof |
| CN107108429A (en) * | 2015-12-23 | 2017-08-29 | 联邦科学与工业研究组织 | Compound |
Non-Patent Citations (1)
| Title |
|---|
| Synthesis of enaminones containing diverse N,Ndisubstitution via simple transamination: a study with sustainable catalyst-free operation;Yong Gao，等;《Research on Chemical Intermediates》;20171231;第43卷(第10期);第5547-5555页 * |
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