CN112500364A - Synthesis process of 3, 4-dichloroisothiazole methyl ketone - Google Patents
Synthesis process of 3, 4-dichloroisothiazole methyl ketone Download PDFInfo
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- CN112500364A CN112500364A CN202110006448.4A CN202110006448A CN112500364A CN 112500364 A CN112500364 A CN 112500364A CN 202110006448 A CN202110006448 A CN 202110006448A CN 112500364 A CN112500364 A CN 112500364A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
- C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
- C07D275/03—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings 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
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Abstract
The invention provides a synthesis process for preparing 3, 4-dichloroisothiazole methyl ketone, and also discloses a purification method of the compound; the chemical structure of the 3, 4-dichloroisothiazole methyl ketone is shown in formula I: i:
Description
Technical Field
The invention relates to an isothiazole methyl ketone derivative, which specifically comprises the following components in part by weight: the invention relates to 3, 4-dichloroisothiazole methyl ketone, and relates to a preparation method and a process route of the compound.
Background
The heterocyclic compound is an important source for the structure development of pesticides, and is a common high-efficiency, low-toxicity and broad-spectrum bioactive lead compound. Most of active molecules reported in the literature have heterocyclic structures. In the related pesticide patents, N-containing heterocycles (pyridine, pyrazole, pyrimidine and the like), sulfur-containing heterocycles, thiazole, fused heterocycles and the like account for more than half of the total number, but N-and S-containing compounds (including thiazole, isothiazole, thiadiazole and the like) often have wide biological activity. 3, 4-dichloroisothiazolemethyl ketone is a key intermediate for many pesticide molecules.
The strobilurin fungicide has broad-spectrum bactericidal activity and has good activity on almost all fungal diseases (ascomycetes, basidiomycetes, oomycetes and fungi imperfecti). In order to find and discover a pesticide lead compound which is more efficient, broad-spectrum, low-toxicity and low-ecological risk and has no cross resistance with the existing bactericide, an isothiazole pharmacophore 3, 4-dichloroisothiazole ring containing N and S is introduced into a methoxyacrylate parent structure, so that an isothiazole oxime ether methoxyacrylate bactericidal candidate compound can be obtained. Biological activity screening finds a plurality of high-activity compounds; 3, 4-dichloroisothiazole methyl ketone is a key intermediate for synthesizing isothiazole oxime ether methoxy acrylate bactericidal compounds. The invention carries out systematic research on the synthesis process of the intermediate, and lays a foundation for the production and industrialization of the series of high-activity compounds (Van Shijin and the like, a class of isothiazole oxime ether methoxy acrylate derivatives, a preparation method and application thereof, the invention patent of the people's republic of China, the application date of which is 3 and 25 in 2016, and the application number of which is 201610185795.7).
The literature reports that the synthetic route of 3, 4-dichloroisothiazole methyl ketone has two routes: 3, 4-dichloroisothiazole-5-formic acid and methoxy methylamine hydrochloride are firstly reacted with each other to obtain a methoxy substituted 3, 4-dichloroisothiazole formamide intermediate under the action of a condensing agent (EDCI), and the intermediate and a methyl Grignard reagent are subjected to substitution reaction in a tetrahydrofuran solvent at minus 30 ℃ to obtain a target product (RSC Advances 2017, 7(6), 3145-one 3151); the method needs methyl Grignard reagent, has high cost, strict control of anhydrous operation, high production difficulty, strict requirement on equipment and poor reaction repeatability. The other route is as follows: 3, 4-dichloroisothiazole-5-formyl chloride and Meldrum's acid are subjected to condensation reaction under the action of alkali to obtain an intermediate, and the intermediate is heated and decarboxylated under the condition of strong acid to obtain a target product (WO 03031240A 1); the yield of the intermediate prepared in the first step of the route is low, only 40 percent, so that the overall yield of the route is low, and the price of the Meldrum's acid is high, so that if the existing synthetic route is used for industrial production, various problems exist, the reaction route is further optimized, and a new route suitable for industrial large-scale production is developed.
The invention improves the synthesis process of the 3, 4-dichloroisothiazole methyl ketone and provides two new synthesis routes; lays a foundation for the deep research and the industrial development of the compound.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: provides a new synthesis process of the 3, 4-dichloroisothiazole methyl ketone, and provides a technical basis and support for industrial production.
The technical scheme adopted by the invention for solving the technical problem is as follows: optimizes the synthesis process route of the intermediate 3, 4-dichloroisothiazole methyl ketone with bactericidal activity.
The chemical structural formula of the 3, 4-dichloroisothiazole methyl ketone is as follows:
two process routes for synthesizing the 3, 4-dichloroisothiazole methyl ketone I of the invention are specifically described as follows:
the specific operation steps for preparing the 3, 4-dichloroisothiazole methyl ketone I by utilizing the beta-keto ester are as follows:
R1selected from: methyl, ethyl, alkyl; the catalyst is selected from: trichloroAluminum oxide, silver tetrafluoroborate, boron trifluoride, sulfur trioxide, and ferric bromide or other lewis acids.
The specific operation steps for preparing the 3, 4-dichloroisothiazole methyl ketone I by utilizing the beta-keto ester are as follows:
compound II (5.0 mmol), catalyst (0.25 mmol), water (0.18g, 10.0 mmol) and 5.0 ml of acetic acid were added to a 100 ml round bottom flask and reacted under reflux for a certain period of time; after the reaction is finished, cooling, standing, filtering off insoluble substances, adding a proper amount of water, extracting with ethyl acetate, combining organic phases, washing with saturated saline solution, and drying with anhydrous sodium sulfate; evaporating the solvent under reduced pressure to obtain a light yellow solid I; the amount of the compound can be enlarged or reduced according to the corresponding proportion, the material ratio A to the catalyst is selected from any proportion between 1000: 1 and 10: 1, the reaction time is selected from any time between 5 hours and 20 hours, and the material ratio A to the water is selected from any proportion between 1: 1 and 1: 5.
The specific operation steps for preparing the 3, 4-dichloroisothiazole methyl ketone I by using the 1, 3-diester are as follows:
R2selected from: methyl, ethyl, alkyl;
selected from: hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, or other strong acids.
The specific operation steps for preparing the 3, 4-dichloroisothiazole methyl ketone I by using the 1, 3-diester are as follows:
dissolving the compound III by using glacial acetic acid, adding a little strong acid for catalysis, and heating for reaction; after the reaction is finished, cooling, standing, filtering off insoluble substances, adding a proper amount of water, extracting with ethyl acetate, combining organic phases, washing with saturated saline solution, and drying with anhydrous sodium sulfate; evaporating the solvent under reduced pressure to obtain a light yellow solid I; the dosage of the compound can be enlarged or reduced according to the corresponding proportion, the material ratio III to the strong acid is selected from any proportion between 1000: 1 and 10: 1, the reaction time is selected from any time between 1 hour and 24 hours, and the reaction temperature is selected from any temperature between 40 ℃ and 120 ℃.
Example 1. synthetic route to 3, 4-dichloroisothiazole methyl ketone I using beta-keto ester:
adding ethyl 3- (3, 4-dichloroisothiazol-5-yl) -3-oxopropanoate A (1.33 g, 5.0 mmol), silver tetrafluoroborate B (0.05 g, 0.25 mmol), water (0.18g, 10.0 mmol) and 5.0 ml of acetic acid into a 100 ml round-bottomed flask, heating and refluxing for a certain time, detecting the completion of the reaction, cooling and standing to filter out insoluble substances, adding an appropriate amount of water, extracting with ethyl acetate, washing the combined organic phases with saturated brine, and drying over anhydrous sodium sulfate; evaporating the solvent under reduced pressure to obtain a light yellow solid I;1H NMR(400MHz，CDCl3) δ 2.65(s, 3H). The dosage of the compound can be enlarged or reduced according to the corresponding proportion, the range of the material ratio A to the silver tetrafluoroborate is selected from any proportion between 1000: 1 and 10: 1, the reaction time is selected from any time between 5 hours and 20 hours, the adding amount range of the material ratio A to the water is selected from any proportion between 1: 1 and 1: 5, and the typical experiment result of condition optimization is shown in table 1. Table 1 shows that the optimized route selected by the present invention is the condition of data display in the first column, and the yield in the whole table is higher than about 40% of the reference in the introduction by at least 10%, therefore, the improvement of the process route is a significant technical progress.
Example 2. synthetic process route for preparing 3, 4-dichloroisothiazole methyl ketone I using 1, 3-diester as raw material:
compound E (1.70 g)5.0 mmol) was dissolved in 5.0 ml of glacial acetic acid, and concentrated sulfuric acid (49 mg, 0.5 mmol) was added thereto and heated under reflux for 6.0 hours; cooling to room temperature, adding appropriate amount of water, extracting with ethyl acetate, mixing organic phases, washing with saturated saline solution, and drying with anhydrous sodium sulfate; evaporating the solvent under reduced pressure to obtain a light yellow solid I;1H NMR(400MHz，CDCl3) δ 2.65(s, 3H); the dosage of the compound can be enlarged or reduced according to the corresponding proportion, the range of the material ratio E to the sulfuric acid is selected from any proportion between 1000: 1 and 10: 1, the reaction time is selected from any time between 5 hours and 24 hours, and the typical experimental result of condition optimization is shown in a table 2. As can be seen from Table 2, the invention screens out two optimized conditions of the route, the conditions shown in the data of the 4 th column and the 13 th column, the condition in the 13 th column greatly reduces the dosage of G, the route is the optimal route of the invention, the yield is higher than about 40% of the reference in the introduction by at least 10%, and the improvement of the process route has obvious technical progress.
TABLE 1 optimization of Process conditions for the preparation of 3, 4-dichloroisothiazole methyl ketone I using beta-keto esters
| Serial number | A/millimole | B/millimole | C/ml | D/millimole | Time per hour | Temperature/degree centigrade | Yield/%) |
| 1 | 5 | 0.5 | 5 | 10 | 12 | 117 | 82 |
| 2 | 5 | 0.25 | 5 | 10 | 12 | 117 | 80 |
| 3 | 5 | 0.05 | 5 | 10 | 12 | 117 | 77 |
| 4 | 5 | 0.025 | 5 | 10 | 12 | 117 | 65 |
| 5 | 5 | 0.005 | 5 | 10 | 12 | 117 | 52 |
| 6 | 5 | 0.05 | 5 | 10 | 24 | 117 | 79 |
| 7 | 5 | 0.025 | 5 | 10 | 24 | 117 | 73 |
| 8 | 5 | 0.005 | 5 | 10 | 24 | 117 | 66 |
| 9 | 5 | 0.05 | 5 | 10 | 12 | 100 | 62 |
| 10 | 5 | 0.05 | 5 | 10 | 12 | 80 | 52 |
| 11 | 5 | 0.05 | 2.5 | 10 | 12 | 117 | 78 |
| 12 | 5 | 0.05 | 1.0 | 10 | 12 | 117 | 53 |
| 13 | 5 | 0.05 | 2.5 | 7.5 | 12 | 117 | 75 |
| 14 | 5 | 0.05 | 2.5 | 7.5 | 15 | 117 | 78 |
| 15 | 5 | 0.05 | 2.5 | 7.5 | 18 | 117 | 79 |
| 16 | 5 | 0.05 | 2.5 | 7.5 | 24 | 117 | 78 |
TABLE 2 optimization of Process conditions for the preparation of 3, 4-dichloroisothiazole methyl ketone I using 1, 3-diester as raw material
| Serial number | E/millimole | F/millimole | G/ml | Time per hour | Temperature/degree centigrade | Yield/%) |
| 1 | 5 | 0.5 | 5 | 12 | 117 | 68 |
| 2 | 5 | 0.5 | 5 | 10 | 117 | 66 |
| 3 | 5 | 0.5 | 5 | 8 | 117 | 67 |
| 4 | 5 | 0.5 | 5 | 6 | 117 | 68 |
| 5 | 5 | 0.5 | 5 | 4 | 117 | 55 |
| 6 | 5 | 0.05 | 5 | 6 | 117 | 65 |
| 7 | 5 | 0.025 | 5 | 6 | 117 | 60 |
| 8 | 5 | 0.01 | 5 | 6 | 117 | 58 |
| 9 | 5 | 0.005 | 5 | 6 | 117 | 45 |
| 10 | 5 | 0.05 | 5 | 6 | 100 | 52 |
| 11 | 5 | 0.05 | 5 | 6 | 80 | 43 |
| 12 | 5 | 0.05 | 2.5 | 6 | 117 | 64 |
| 13 | 5 | 0.05 | 1.0 | 6 | 117 | 62 |
Claims (2)
1. The synthesis process route for preparing the 3, 4-dichloroisothiazole methyl ketone I by utilizing the beta-keto ester is characterized by comprising the following reaction route:
R1selected from: methyl, ethyl, alkyl; the catalyst is selected from: aluminum trichloride, silver tetrafluoroborate, boron trifluoride, sulfur trioxide, ferric bromide and other lewis acids;
the specific operation steps for preparing the 3, 4-dichloroisothiazole methyl ketone I by utilizing the beta-keto ester are as follows:
compound II (5.0 mmol), catalyst (0.25 mmol), water (0.18g, 10.0 mmol) and 5.0 ml of acetic acid were added to a 100 ml round bottom flask and reacted under reflux for a certain period of time; after the reaction is finished, cooling, standing, filtering off insoluble substances, adding a proper amount of water, extracting with ethyl acetate, combining organic phases, washing with saturated saline solution, and drying with anhydrous sodium sulfate; evaporating the solvent under reduced pressure to obtain a light yellow solid I; the amount of the compound can be enlarged or reduced according to the corresponding proportion, the material ratio A to the catalyst is selected from any proportion between 1000: 1 and 10: 1, the reaction time is selected from any time between 5 hours and 20 hours, and the material ratio A to the water is selected from any proportion between 1: 1 and 1: 5.
2. The synthesis process route for preparing 3, 4-dichloroisothiazole methyl ketone I by using 1, 3-diester is characterized by comprising the following reaction route:
R2selected from: methyl, ethyl, alkyl;
selected from: hydrochloric acid, sulfuric acid, p-toluenesulfonic acid and other strong acids;
the specific operation steps for preparing the 3, 4-dichloroisothiazole methyl ketone I by using the 1, 3-diester are as follows:
dissolving the compound III by using glacial acetic acid, adding a little strong acid for catalysis, and heating for reaction; after the reaction is finished, cooling, standing, filtering off insoluble substances, adding a proper amount of water, extracting with ethyl acetate, combining organic phases, washing with saturated saline solution, and drying with anhydrous sodium sulfate; evaporating the solvent under reduced pressure to obtain a light yellow solid I; the dosage of the compound can be enlarged or reduced according to the corresponding proportion, the material ratio III to the strong acid is selected from any proportion between 1000: 1 and 10: 1, the reaction time is selected from any time between 1 hour and 24 hours, and the reaction temperature is selected from any temperature between 40 ℃ and 120 ℃.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102942565A (en) * | 2012-11-06 | 2013-02-27 | 江西天人生态股份有限公司 | 3,4-dichloro isothiazole derivatives, their preparation method and application |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102942565A (en) * | 2012-11-06 | 2013-02-27 | 江西天人生态股份有限公司 | 3,4-dichloro isothiazole derivatives, their preparation method and application |
Non-Patent Citations (1)
| Title |
|---|
| CHEN, LAI ET AL: "Synthesis and fungicidal activity of 3,4-dichloroisothiazole based strobilurins as potent fungicide candidates", 《RSC ADVANCES》 * |
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Application publication date: 20210316 |