CN112645884B - Synthetic method of 3, 6-difluoro-4-methylpyridazine - Google Patents
Synthetic method of 3, 6-difluoro-4-methylpyridazine Download PDFInfo
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- CN112645884B CN112645884B CN202110158961.5A CN202110158961A CN112645884B CN 112645884 B CN112645884 B CN 112645884B CN 202110158961 A CN202110158961 A CN 202110158961A CN 112645884 B CN112645884 B CN 112645884B
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- methylpyridazine
- difluoro
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members 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
- C07D237/12—Halogen atoms or nitro radicals
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- Pyridine Compounds (AREA)
Abstract
The invention belongs to the technical field of medical intermediates, and particularly relates to a synthetic method of 3, 6-difluoro-4-methylpyridazine. The synthesis method comprises the step of taking 3, 6-dichloro-4-methylpyridazine as a raw material, and reacting the 3, 6-dichloro-4-methylpyridazine with potassium fluoride in an organic solvent to obtain the 3, 6-difluoro-4-methylpyridazine.
Description
Technical Field
The invention belongs to the technical field of medical intermediates, and particularly relates to a synthetic method of 3, 6-difluoro-4-methylpyridazine.
Background
Pyridazine is an important aromatic ring compound, is widely found in natural product medical intermediates and pesticides, and has strong physiological activities of resisting virus, reducing blood pressure and the like. In the prior art, the synthesis process of the pyridazine ring is complex and has low yield, and research and improvement on the synthesis process become necessary.
3, 6-difluoro-4-methylpyridazine is one kind of pyridazine, and its synthesis process and relevant derivative have wide application in medicinal chemistry and organic synthesis. At present, the synthesis method of 3, 6-difluoro-4-methylpyridazine has few reports in documents. Therefore, it is necessary to develop a synthesis method which has easily available raw materials, convenient operation, easy control of reaction, proper overall yield and suitability for industrial production.
Disclosure of Invention
The technical problems to be solved by the invention are as follows: in order to solve the problems, a method for synthesizing 3, 6-difluoro-4-methylpyridazine is provided.
In order to solve the technical problems, the invention adopts the following technical scheme:
a synthetic method of 3, 6-difluoro-4-methylpyridazine, wherein the structure of the 3, 6-difluoro-4-methylpyridazine is as follows:
the synthesis method comprises the step of taking 3, 6-dichloro-4-methylpyridazine as a raw material, and reacting the 3, 6-dichloro-4-methylpyridazine with potassium fluoride in an organic solvent to obtain the 3, 6-difluoro-4-methylpyridazine.
The synthesis method comprises the steps of adding 3, 6-dichloro-4-methylpyridazine, potassium fluoride and an organic solvent into a reactor, heating to 130-140 ℃ under the protection of nitrogen, and reacting to obtain the 3, 6-difluoro-4-methylpyridazine.
The organic solvent is N, N-dimethylformamide.
The mass ratio of the potassium fluoride to the 3, 6-dichloro-4-methylpyridazine is 1-3: 1.
The solid-liquid g/mL ratio of the 3, 6-dichloro-4-methylpyridazine to the organic solvent is 1: 5-9.
Compared with other methods, the method has the beneficial technical effects that:
(1) the invention provides a synthetic method of 3, 6-difluoro-4-methylpyridazine, and provides a synthetic route for the synthetic method of 3, 6-difluoro-4-methylpyridazine;
(2) the synthetic method of the 3, 6-difluoro-4-methylpyridazine is short in route, reasonable in design, simple to operate and easy to control;
(3) the product obtained by the method has high yield.
Detailed Description
The organic solvent is N, N-dimethylformamide.
A synthesis method of 3, 6-difluoro-4-methylpyridazine comprises the steps of taking materials according to the mass ratio of potassium fluoride to 3, 6-dichloro-4-methylpyridazine of 1-3: 1, 3, 6-dichloro-4-methylpyridazine and the solid-liquid g/mL ratio of an organic solvent of 1: 5-9, adding 3, 6-dichloro-4-methylpyridazine, potassium fluoride and the organic solvent into a reactor, carrying out nitrogen protection, heating to 130-140 ℃, and reacting for 4-8 hours to obtain the 3, 6-difluoro-4-methylpyridazine.
Example 1
The organic solvent is N, N-dimethylformamide.
A synthesis method of 3, 6-difluoro-4-methylpyridazine comprises the steps of adding 100g of 3, 6-dichloro-4-methylpyridazine, 110g of potassium fluoride and 850mL of organic solvent into a reactor, heating to 135 ℃ under the protection of nitrogen, reacting for 6 hours, detecting by TLC, finishing the reaction of raw materials, filtering, distilling mother liquor under reduced pressure (external temperature 70 ℃), distilling to obtain a mixture of a product and DMF, adding the distilled fraction into 1000mL of water, extracting with ethyl acetate (1000 mL of 2), concentrating, loading the mixture to a column by a wet method, collecting a product spot, and concentrating to obtain 75.6g of light yellow oily matter, namely the 3, 6-difluoro-4-methylpyridazine, wherein the yield is 94.7%, and the purity is 97.6%.
1H NMR（CDCl3）: 7.18(dd, J=6.8, 0.8Hz, 1H), 2.41(s, 3H)。
Example 2
The organic solvent is N, N-dimethylformamide.
A synthesis method of 3, 6-difluoro-4-methylpyridazine comprises the steps of adding 100g of 3, 6-dichloro-4-methylpyridazine, 110g of potassium fluoride and 850mL of organic solvent into a reactor, heating to 140 ℃ under the protection of nitrogen, reacting for 8 hours, detecting by TLC, finishing the reaction of raw materials, filtering, distilling mother liquor under reduced pressure (external temperature 70 ℃), distilling to obtain a mixture of a product and DMF, adding the distilled fraction into 1000mL of water, extracting with ethyl acetate (1000 mL of 2), concentrating, loading by a wet method, passing through a column, collecting a product point, and concentrating to obtain 77.2g of light yellow oily matter, namely the 3, 6-difluoro-4-methylpyridazine, wherein the yield is 96.7% and the purity is 98.8%.
1H NMR（CDCl3）: 7.18(dd, J=6.8, 0.8Hz, 1H), 2.41(s, 3H)。
Example 3
The organic solvent is N, N-dimethylformamide.
A synthesis method of 3, 6-difluoro-4-methylpyridazine comprises the steps of adding 100g of 3, 6-dichloro-4-methylpyridazine, 110g of potassium fluoride and 850mL of organic solvent into a reactor, heating to 130 ℃ under the protection of nitrogen, reacting for 4 hours, detecting by TLC, finishing the reaction of raw materials, filtering, distilling mother liquor under reduced pressure (external temperature 70 ℃), distilling to obtain a mixture of a product and DMF, adding the distilled fraction into 1000mL of water, extracting with ethyl acetate (1000 mL of 2), concentrating, loading the mixture to a column by a wet method, collecting a product spot, and concentrating to obtain 76.5g of light yellow oily matter, namely the 3, 6-difluoro-4-methylpyridazine, wherein the yield is 95.8% and the purity is 99.1%.
1H NMR（CDCl3）: 7.18(dd, J=6.8, 0.8Hz, 1H), 2.41(s, 3H)。
Claims (5)
1. A synthetic method of 3, 6-difluoro-4-methylpyridazine, wherein the structure of the 3, 6-difluoro-4-methylpyridazine is as follows:
the synthesis method is characterized in that 3, 6-dichloro-4-methylpyridazine is used as a raw material, and potassium fluoride and the 3, 6-dichloro-4-methylpyridazine react in an organic solvent to obtain the 3, 6-difluoro-4-methylpyridazine.
2. The method for synthesizing 3, 6-difluoro-4-methylpyridazine according to claim 1, wherein the method comprises the steps of adding 3, 6-dichloro-4-methylpyridazine, potassium fluoride and an organic solvent into a reactor, heating to 130-140 ℃ under the protection of nitrogen, and reacting to obtain 3, 6-difluoro-4-methylpyridazine.
3. The method for synthesizing 3, 6-difluoro-4-methylpyridazine according to claim 1 or 2, wherein the organic solvent is N, N-dimethylformamide.
4. The method for synthesizing 3, 6-difluoro-4-methylpyridazine according to claim 1 or 2, wherein the mass ratio of the potassium fluoride to the 3, 6-dichloro-4-methylpyridazine is 1-3: 1.
5. The method for synthesizing 3, 6-difluoro-4-methylpyridazine according to claim 1 or 2, wherein the solid-liquid g/mL ratio of the 3, 6-dichloro-4-methylpyridazine to the organic solvent is 1:5 to 9.
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| CN112645884B true CN112645884B (en) | 2022-03-11 |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102432545A (en) * | 2011-11-22 | 2012-05-02 | 太仓市运通化工厂 | Method for synthetizing 3-amino-6-methylpyridazine |
| CN104447569A (en) * | 2014-11-05 | 2015-03-25 | 定陶县友帮化工有限公司 | Method for synthetizing 3,6-dichloropyridazine |
| CN104788384A (en) * | 2015-03-31 | 2015-07-22 | 山东友帮生化科技有限公司 | Synthesis method of 3-hydroxy-6-chloropyridazine |
| CN105254633A (en) * | 2015-09-29 | 2016-01-20 | 山东友帮生化科技有限公司 | Synthesis method of imidazo[1, 2-b]pyridazine-3-carbonitrile |
| CN110240568A (en) * | 2019-04-01 | 2019-09-17 | 兰州大学 | Three replace pyridazine analog derivative and preparation method thereof |
-
2021
- 2021-02-05 CN CN202110158961.5A patent/CN112645884B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102432545A (en) * | 2011-11-22 | 2012-05-02 | 太仓市运通化工厂 | Method for synthetizing 3-amino-6-methylpyridazine |
| CN104447569A (en) * | 2014-11-05 | 2015-03-25 | 定陶县友帮化工有限公司 | Method for synthetizing 3,6-dichloropyridazine |
| CN104788384A (en) * | 2015-03-31 | 2015-07-22 | 山东友帮生化科技有限公司 | Synthesis method of 3-hydroxy-6-chloropyridazine |
| CN105254633A (en) * | 2015-09-29 | 2016-01-20 | 山东友帮生化科技有限公司 | Synthesis method of imidazo[1, 2-b]pyridazine-3-carbonitrile |
| CN110240568A (en) * | 2019-04-01 | 2019-09-17 | 兰州大学 | Three replace pyridazine analog derivative and preparation method thereof |
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