CN108191765B - Preparation method of enilconazole - Google Patents
Preparation method of enilconazole Download PDFInfo
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- CN108191765B CN108191765B CN201711427596.3A CN201711427596A CN108191765B CN 108191765 B CN108191765 B CN 108191765B CN 201711427596 A CN201711427596 A CN 201711427596A CN 108191765 B CN108191765 B CN 108191765B
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Abstract
The invention discloses a preparation method of enilconazole, which comprises the following steps: adding 2, 4-dichloro-2' -chloroacetophenone, a reducing agent, an organic base and a catalyst into a reaction container, controlling the temperature at 65-75 ℃ to react for 8-10h, concentrating, adding sodium hydroxide, dimethylacetamide and imidazole, reacting for 4-6 h at 95-105 ℃, cooling, dropwise adding allyl chloride, reacting for 5-7 h at 100-110 ℃, and performing water precipitation and suction filtration to obtain an enilconazole crude product; recrystallizing the crude product with ethanol and drying to obtain dried product of enilconazole; the reducing agent is formic acid or isopropanol, and the catalyst is RuCl2(pph3)3. Compared with the commonly used sodium borohydride, the method has the advantages of high yield, less impurities and mild reaction, and has the potential of industrial production.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a novel preparation method of enilconazole.
Background
Enconazole (C)14H14Cl2N2O) also known as imazalil, the chemical name of which is 1- [2- (2, 4-dichlorophenyl) -2- (2-allyloxy) ethyl]the-1H-imidazole is a systemic benzimidazole bactericide developed by janssenpharmaceuticala, has control effects on fungal diseases of plants such as fruits, vegetables and the like, and particularly has remarkable effects on common penicilliosis and green mold. Because of the characteristics of high efficiency, broad spectrum and low toxicity, the preservative has been widely applied to the preservation of fruits and vegetables, and has wide prospect. The molecular weight of the enilconazole is 297.2, and the structural formula is as follows:
the currently reported synthetic method of enilconazole generally takes 2, 4-dichloro-2' -chloroacetophenone as a raw material or an intermediate product, reduces carbonyl to hydroxyl by sodium borohydride, and then sequentially uses imidazole and allyl chloride for substitution reaction to finally generate a product. The process has the difficulties of more impurities and lower yield in the reduction step, and the sodium borohydride reduction feeding process needs to be added in batches at low temperature, generates a large amount of waste gas, and has harsh conditions, high operation strength and certain dangerousness. Therefore, the new development significance of the reduction step is significant.
Disclosure of Invention
The invention aims to solve the technical problem of providing a novel preparation method of enilconazole aiming at the defects of the prior art or products, and the method has the advantages of mild conditions, simple operation, higher yield and product purity, simple post-treatment mode and easy realization of large-scale production.
The invention provides a preparation method of enilconazole, which comprises the following steps:
adding 2, 4-dichloro-2' -chloroacetophenone, a reducing agent, an organic base and a catalyst into a reaction container, controlling the temperature at 65-75 ℃ to react for 8-10h, concentrating, adding sodium hydroxide, dimethylacetamide and imidazole, reacting for 4-6 h at 95-105 ℃, cooling, dropwise adding allyl chloride, reacting for 5-7 h at 100-110 ℃, and purifying to obtain enilconazole; the reducing agent is formic acid or isopropanol, and the catalyst is RuCl2(pph3)3。
The invention has the beneficial effects that: the invention adopts mild reducing agent and novel catalyst RuCl2(pph3)3The method realizes the reduction of the substrate by hydrogen given by the organic hydrogen source and achieves the reaction aim in a hydrogen transfer mode, compared with the conventional reduction by sodium borohydride, the method has the advantages of milder reaction conditions, easier reaction, less generated impurities and easy removal, greatly reduced operation difficulty, high product yield of more than 60 percent and high purity of more than 98 percent, suitability for industrial production and wide application prospect。
Drawings
FIG. 1 shows a refined enrconazole obtained in example 11H NMR spectrum.
FIG. 2 is a gas chromatographic chart of a refined enilconazole obtained in example 1.
Detailed Description
The invention provides a preparation method of enilconazole, which comprises the following steps:
adding 2, 4-dichloro-2' -chloroacetophenone, a reducing agent, an organic base and a catalyst into a reaction container, controlling the temperature at 65-75 ℃ to react for 8-10h, concentrating, adding sodium hydroxide, dimethylacetamide and imidazole, reacting for 4-6 h at 95-105 ℃, cooling, dropwise adding allyl chloride, reacting for 5-7 h at 100-110 ℃, and purifying to obtain enilconazole; the reducing agent is formic acid or isopropanol, and the catalyst is RuCl2(pph3)3。
The reaction formula of the above reaction is as follows:
preferably, the molar ratio of the 2,2 ', 4' -trichloroacetophenone to the reducing agent to the organic base to the catalyst to the sodium hydroxide to the dimethylacetamide to the imidazole to the allyl chloride is 1: 18-22: 0.4-0.6: 0.03-0.07: 1.5-2.5: 9-11: 1.5-1.7.
More preferably, in one embodiment of the present invention, the molar ratio of the 2,2 ', 4' -trichloroacetophenone, the reducing agent, the organic base, the catalyst, the sodium hydroxide, the dimethylacetamide, the imidazole and the allyl chloride is 1:20:0.5:0.05:2:10:1.6: 1.6.
Preferably, after the substrate is reduced, sodium hydroxide, dimethylacetamide and imidazole are added to react at 100 ℃ for 5h, and after cooling, allyl chloride is added dropwise to react at 105 ℃ for 6 h.
Preferably, the organic base is triethylamine or DIPEA.
Preferably, the purification step comprises: and cooling after the reaction is finished, adding water with the volume being twice that of the reaction system, stirring for 5-15 min, performing suction filtration to obtain an eniconazole crude product, and recrystallizing the eniconazole crude product with ethanol to obtain an eniconazole product.
Preferably, the cooling is to room temperature, and the room temperature is generally 15-30 ℃.
The preparation method of enilconazole provided by the present invention will be further described with reference to the following specific examples. The following examples are illustrative only and are not to be construed as limiting the invention.
The experimental procedures in the following examples are conventional unless otherwise specified. The experimental materials used in the following examples were all commercially available unless otherwise specified.
Example one
The embodiment provides a preparation method of enilconazole, which comprises the following steps:
120g (2.0mol) of isopropanol, 22.3g (0.1mol) of 2, 4-dichloro-2' -chloroacetophenone, 6.5g (0.05mol) of DIPEA and RuCl are sequentially added under stirring2(pph3)34.8g (0.005mol) was put into a 250ml three-necked flask, and the temperature was raised to 65 ℃ to conduct the thermal reaction for 10 hours. After the reaction is finished, the temperature is reduced to 50 ℃, the reaction is steamed under negative pressure until no liquid drops, and the temperature is reduced to room temperature. Adding 87g (1.0mol) of DMA, 8g (0.2mol) of sodium hydroxide and 10.9g (0.16mol) of imidazole, heating to 100 ℃, keeping the temperature for reaction for 5 hours, cooling to room temperature, dropwise adding 12g (0.16mol) of allyl chloride, heating to 105 ℃, keeping the temperature for reaction for 6 hours. And after the reaction is finished, cooling to room temperature, adding 160ml of water, performing suction filtration to obtain an eniconazole crude product, adding 45ml of ethanol into the eniconazole crude product, heating and refluxing for 1h, cooling to room temperature, and performing suction filtration to obtain 13.5g of eniconazole refined product, wherein the yield is 60.54%, the liquid phase analysis purity is not less than 98%, and the melting point is 50.8-52.1 ℃.
Subjecting the obtained refined enrazole product to1H NMR characterization is carried out, the obtained result is shown in figure 1,1HNMR(400MHz，CDCl3)：3.72～3.94(m，2H，＝CH2)；3.95～4.21(m，2H，CH2)；4.92～5.14(m，2H，OCH2)；5.15～5.19(m，1H，CHO)；5.70～5.80(m，1H，＝CH)；6.93(s，1H，Het)；7.01(s，1H,Het)；7.24～7.30(m，2H，Ar)；7.30～7.44(m，2H，Ar+Het)。
the obtained refined enilconazole product was subjected to gas chromatography, and the results are shown in the attached FIG. 2 and Table 1.
TABLE 1 gas chromatography characterization of the refined enilconazole product obtained in example 1
| Retention time | Area of | Percentage of area | Peak height | Percentage of peak height |
| 5.383 | 103706 | 0.07 | 105180 | 0.25 |
| 5.485 | 642 | 0.00 | 1233 | 0.00 |
| 5.963 | 92352 | 0.07 | 46078 | 0.11 |
| 6.437 | 211633 | 0.15 | 134356 | 0.32 |
| 6.595 | 138509481 | 99.00 | 40819978 | 98.20 |
| 6.969 | 66672 | 0.05 | 51320 | 0.12 |
| 7.283 | 521198 | 0.37 | 306618 | 0.74 |
| 10.318 | 399203 | 0.29 | 101872 | 0.25 |
| Total of | 139904887 | 100 | 41566635 | 100.00 |
Example two
The embodiment provides a preparation method of enilconazole, which comprises the following steps: 92g (2.0mol) of formic acid, 22.5g (0.1mol) of 2, 4-dichloro-2' -chloroacetophenone, 5g (0.05mol) of triethylamine and RuCl are added in sequence under stirring2(pph3)34.8g (0.005mol) was put into a 250ml three-necked flask, and the temperature was raised to 75 ℃ to conduct a heat-retaining reaction for 8 hours. After the reaction is finished, the temperature is reduced to 50 ℃, the reaction is steamed under negative pressure until no liquid drops, and the temperature is reduced to room temperature. Adding 87g (1.0mol) of DMA, 8g (0.2mol) of sodium hydroxide and 10.9g (0.16mol) of imidazole, heating to 100 ℃, keeping the temperature for reaction for 5 hours, cooling to room temperature, dropwise adding 12g (0.16mol) of allyl chloride, heating to 105 ℃, keeping the temperature for reaction for 6 hours. And after the reaction is finished, cooling to room temperature, adding 150ml of water, performing suction filtration to obtain an eniconazole crude product, adding 46ml of ethanol into the eniconazole crude product, heating and refluxing for 1h, cooling to room temperature, and performing suction filtration to obtain 14.1g of eniconazole refined product, wherein the yield is 64.23%, the liquid phase analysis purity is not less than 98%, and the melting point is 51.0-52.1 ℃.
EXAMPLE III
The embodiment provides a preparation method of enilconazole, which comprises the following steps: 185g (4.0mol) of formic acid, 45.1g (0.2mol) of 2, 4-dichloro-2' -chloroacetophenone, 10g (0.1mol) of triethylamine and RuCl are added in sequence under stirring2(pph3)39.5g (0.01mol) was put into a 500ml three-necked flask, and the temperature was raised to 70 ℃ to conduct a heat-insulating reaction for 9 hours. After the reaction is finished, the temperature is reduced to 50 ℃, the reaction is steamed under negative pressure until no liquid drops, and the temperature is reduced to room temperature. Adding 175g (2.0mol) of DMA, 16g (0.4mol) of sodium hydroxide and 22g (0.32mol) of imidazole, heating to 100 ℃, keeping the temperature for reaction for 5 hours, cooling to room temperature, dropwise adding 24g (0.32mol) of allyl chloride, heating to 105 ℃, keeping the temperature for reaction for 6 hours. And after the reaction is finished, cooling to room temperature, adding 320ml of water, performing suction filtration to obtain an eniconazole crude product, adding 100ml of ethanol into the eniconazole crude product, heating and refluxing for 1h, cooling to room temperature, and performing suction filtration to obtain 28.7g of eniconazole refined product, wherein the yield is 64.4%, the liquid phase analysis purity is not less than 98%, and the melting point is 50.9-52.0 ℃.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (5)
1. A preparation method of enilconazole is characterized in that: the method comprises the following steps:
adding 2, 4-dichloro-2' -chloroacetophenone, a reducing agent, an organic base and a catalyst into a reaction container, controlling the temperature at 65-75 ℃ to react for 8-10h, concentrating, adding sodium hydroxide, dimethylacetamide and imidazole, reacting for 4-6 h at 95-105 ℃, cooling, dropwise adding allyl chloride, reacting for 5-7 h at 100-110 ℃, and purifying to obtain enilconazole; the reducing agent is formic acid or isopropanol, and the catalyst is RuCl2(pph3)3(ii) a The molar ratio of the 2,2 ', 4' -trichloroacetophenone to the reducing agent to the organic base to the catalyst to the sodium hydroxide to the dimethylacetamide to the imidazole to the allyl chloride is 1:20:0.5:0.05:2:10:1.6: 1.6.
2. The method of preparing eniconazole according to claim 1, wherein: adding sodium hydroxide, dimethylacetamide and imidazole, reacting at 100 ℃ for 5h, cooling, dropwise adding allyl chloride, and reacting at 105 ℃ for 6 h.
3. The method for preparing enilconazole according to any one of claims 1 to 2, wherein: the organic base is triethylamine or DIPEA.
4. The method of preparing eniconazole according to claim 1, wherein: the purification step comprises: and cooling after the reaction is finished, adding water with the volume being twice that of the reaction system, stirring for 5-15 min, performing suction filtration to obtain an eniconazole crude product, and recrystallizing the eniconazole crude product with ethanol to obtain an eniconazole product.
5. The method of preparing eniconazole according to claim 1, wherein: and cooling to 15-30 ℃.
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| CN110437154A (en) * | 2019-09-10 | 2019-11-12 | 武汉川泰科技有限公司 | A kind of preparation method of enilconazole bulk pharmaceutical chemicals |
| CN110845416A (en) * | 2019-11-19 | 2020-02-28 | 武汉回盛生物科技股份有限公司 | O-allylation method of α -diaryl substituted ethanol |
| CN111012740A (en) * | 2019-12-26 | 2020-04-17 | 武汉回盛生物科技股份有限公司 | Enconazole liquid preparation for external use and preparation method thereof |
| CN114409600A (en) * | 2022-01-19 | 2022-04-29 | 武汉回盛生物科技股份有限公司 | Synthetic method of enilconazole |
| CN116082245A (en) * | 2022-12-26 | 2023-05-09 | 武汉工程大学 | Enconazole crystal and preparation method and application thereof |
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| CN101781294A (en) * | 2010-03-10 | 2010-07-21 | 天津药物研究院 | Imidazole derivative, and preparation method and application thereof |
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| CN101781294A (en) * | 2010-03-10 | 2010-07-21 | 天津药物研究院 | Imidazole derivative, and preparation method and application thereof |
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