CN117229278A - Synthesis method of trifluoromethyl-bis-isothiazolinone-difluoromethoxy pyrazole compound - Google Patents
Synthesis method of trifluoromethyl-bis-isothiazolinone-difluoromethoxy pyrazole compound Download PDFInfo
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- CN117229278A CN117229278A CN202311200573.4A CN202311200573A CN117229278A CN 117229278 A CN117229278 A CN 117229278A CN 202311200573 A CN202311200573 A CN 202311200573A CN 117229278 A CN117229278 A CN 117229278A
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- trifluoromethyl
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- 238000001308 synthesis method Methods 0.000 title claims abstract description 10
- -1 trifluoromethyl-difluoromethoxy pyrazole Chemical compound 0.000 claims abstract description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 51
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 230000002194 synthesizing effect Effects 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- NBZBKCUXIYYUSX-UHFFFAOYSA-N iminodiacetic acid Chemical compound OC(=O)CNCC(O)=O NBZBKCUXIYYUSX-UHFFFAOYSA-N 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 7
- WQRHIGNAKDJJKN-UHFFFAOYSA-N 2-methyl-5-(trifluoromethyl)-1h-pyrazol-3-one Chemical compound CN1NC(C(F)(F)F)=CC1=O WQRHIGNAKDJJKN-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 4
- OCJKUQIPRNZDTK-UHFFFAOYSA-N ethyl 4,4,4-trifluoro-3-oxobutanoate Chemical compound CCOC(=O)CC(=O)C(F)(F)F OCJKUQIPRNZDTK-UHFFFAOYSA-N 0.000 claims description 4
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical compound CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 3
- VOPWNXZWBYDODV-UHFFFAOYSA-N Chlorodifluoromethane Chemical compound FC(F)Cl VOPWNXZWBYDODV-UHFFFAOYSA-N 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 239000012043 crude product Substances 0.000 claims description 3
- 238000006386 neutralization reaction Methods 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 238000010898 silica gel chromatography Methods 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 2
- 241000222122 Candida albicans Species 0.000 abstract description 7
- 241000233866 Fungi Species 0.000 abstract description 7
- 229940095731 candida albicans Drugs 0.000 abstract description 7
- 241000813090 Rhizoctonia solani Species 0.000 abstract description 5
- 241000223261 Trichoderma viride Species 0.000 abstract description 5
- 241000222178 Candida tropicalis Species 0.000 abstract description 4
- 230000004071 biological effect Effects 0.000 abstract description 4
- 230000002401 inhibitory effect Effects 0.000 abstract description 4
- 241000894120 Trichoderma atroviride Species 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 3
- 230000005764 inhibitory process Effects 0.000 abstract description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 9
- 230000000843 anti-fungal effect Effects 0.000 description 7
- 238000000605 extraction Methods 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 230000035484 reaction time Effects 0.000 description 6
- 229940121375 antifungal agent Drugs 0.000 description 5
- 239000000203 mixture Substances 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- MGJURKDLIJVDEO-UHFFFAOYSA-N formaldehyde;hydrate Chemical compound O.O=C MGJURKDLIJVDEO-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- VUWCWMOCWKCZTA-UHFFFAOYSA-N 1,2-thiazol-4-one Chemical class O=C1CSN=C1 VUWCWMOCWKCZTA-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 241001045770 Trichophyton mentagrophytes Species 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000003113 dilution method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- XNZFUKOVJVOLPE-UHFFFAOYSA-N furan;pyridine Chemical class C=1C=COC=1.C1=CC=NC=C1 XNZFUKOVJVOLPE-UHFFFAOYSA-N 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
Abstract
The invention relates to the technical field of biological medicines, and discloses a synthesis method of trifluoromethyl-bis-isothiazolinone-difluoromethoxy pyrazole compound, wherein the trifluoromethyl-bis-isothiazolinone-difluoromethoxy pyrazole compound contains trifluoromethyl-difluoromethoxy pyrazole and an active structure of bis-benzisothiazolinone, and has good inhibition effect on fungi such as candida albicans, candida tropicalis, trichoderma viride, trichoderma atroviride, rhizoctonia solani and the like, the minimum inhibitory concentration on candida albicans is only 0.78ug/mL, and the biological activity of the fungi is excellent.
Description
Technical Field
The invention relates to the technical field of biological medicines, in particular to a method for synthesizing trifluoromethyl-bis-isothiazolinone-difluoromethoxy pyrazole compounds.
Background
The fungi mainly comprise candida albicans, trichoderma viride, rhizoctonia solani and the like, the daily life and the field of the breeding industry are affected by fungus infection, the health and the safety of human bodies are affected, the plant diseases and the like are caused, and the development of novel antifungal compounds has important significance. The existing antifungal drugs mainly comprise pyrazole compounds, pyridine furan compounds, isothiazolinone compounds and the like.
1-methyl-3-trifluoromethyl-4-hydroxymethyl-5-difluoromethoxy-1-H-pyrazole is an important compound intermediate, can be used for synthesizing compounds with biological activities such as herbicides, antibacterial agents and the like, and is a research hot spot for preparing compounds with biological activities such as antifungal activity by synthesizing 1-methyl-3-trifluoromethyl-4-hydroxymethyl-5-difluoromethoxy-1-H-pyrazole as an intermediate through a simple and efficient strategy.
Disclosure of Invention
The invention solves the technical problems that: provides a simple modified trifluoromethyl-bisisothiazolinone-difluoromethoxy pyrazole compound synthesis method, which has excellent antifungal activity.
The technical scheme of the invention is as follows:
the synthesis method of the trifluoromethyl-bis-isothiazolinone-difluoromethoxy pyrazole compound is characterized in that the structural formula of the trifluoromethyl-bis-isothiazolinone-difluoromethoxy pyrazole compound is as follows:
the synthesis method comprises the following steps:
s1, adding 1-methyl-3-trifluoromethyl-4-chloromethyl-5-difluoromethoxy-1-H-pyrazole and iminodiacetic acid into tetrahydrofuran, stirring, dissolving, dropwise adding a sodium hydroxide aqueous solution, concentrating after reaction to remove tetrahydrofuran, dropwise adding hydrochloric acid solution to pH 4-5, adding ethyl acetate, oscillating for extraction, standing for layering, concentrating an ethyl acetate organic phase, and drying to obtain a trifluoromethyl-bis (diacetic acid amine) -difluoromethoxy pyrazole intermediate. The structure is that
S2, adding trifluoromethyl-bis (diacetic acid amine) -difluoromethoxy pyrazole intermediate into dichloromethane, wherein the structural formula isAfter stirring and dissolving, adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole, concentrating after reaction to remove dichloromethane, separating and purifying the crude product by silica gel column chromatography, wherein the eluent is V (ethyl acetate): V (petroleum ether) =1:9 by volume ratio, thus obtaining the trifluoromethyl-bisisothiazolinone-difluoromethoxypyrazole compound.
Preferably, the molar ratio of the 1-methyl-3-trifluoromethyl-4-chloromethyl-5-difluoromethoxy-1-H-pyrazole and iminodiacetic acid in the S1 is 1:0.8-1.4.
Preferably, the mass fraction of the sodium hydroxide aqueous solution in the S1 is 15-40%.
Preferably, the reaction in S1 is carried out at a temperature of 40-70℃for 3-12h.
Preferably, the molar ratio of the trifluoromethyl-bis (diacetic acid amine) -difluoromethoxy pyrazole intermediate to the hydroxyethyl benzisothiazolinone in the S2 is 1:1.5-3.
Preferably, the reaction in S2 is carried out at a temperature of 15-40℃for 4-18h.
Preferably, the synthesis method of the 1-methyl-3-trifluoromethyl-4-chloromethyl-5-difluoromethoxy-1-H-pyrazole comprises the following steps:
(1) Adding ethyl trifluoroacetoacetate and methyl hydrazine into ethanol, dropwise adding concentrated hydrochloric acid, refluxing at 70-85 ℃ for 36-48h, cooling, adding water and ethyl acetate, oscillating for extraction, standing for layering, concentrating an ethyl acetate organic phase, and drying to obtain a 1-methyl-3-trifluoromethyl-5-hydroxy-pyrazole intermediate; the structure is that
(2) Adding 1-methyl-3-trifluoromethyl-5-hydroxy-pyrazole intermediate into potassium hydroxide solution with mass fraction of 20-30%, dropwise adding formaldehyde aqueous solution with mass fraction of 37%,stirring for reaction for 1-2H, adding 20-30% potassium hydroxide solution and acetonitrile, introducing chlorodifluoromethane, continuing to react for 2-3H, adding hydrochloric acid solution for neutralization, adding ethyl acetate, oscillating for extraction, standing for layering, concentrating ethyl acetate organic phase, and drying to obtain 1-methyl-3-trifluoromethyl-4-hydroxymethyl-5-difluoromethoxy-1-H-pyrazole intermediate with a structural formula of
(3) Adding 1-methyl-3-trifluoromethyl-4-hydroxymethyl-5-difluoromethoxy-1-H-pyrazole into thionyl chloride, reacting for 1-3H at room temperature, concentrating under reduced pressure, washing with diethyl ether, and drying to obtain a 1-methyl-3-trifluoromethyl-4-chloromethyl-5-difluoromethoxy-1-H-pyrazole intermediate; the structure is that
The invention has the technical effects that: according to the invention, ethyl trifluoroacetoacetate, methyl hydrazine, formaldehyde water and the like are used as reaction raw materials to synthesize a 1-methyl-3-trifluoromethyl-4-chloromethyl-5-difluoromethoxy-1-H-pyrazole intermediate; then reacts with iminodiacetic acid in a potassium hydroxide catalytic system to obtain a trifluoromethyl-bis (diacetic acid amine) -difluoromethoxy pyrazole intermediate, finally carries out esterification reaction with hydroxyethyl benzisothiazolinone, optimizes and screens the reaction conditions to obtain a trifluoromethyl-bis (isothiazolinone) -difluoromethoxy pyrazole compound with high yield, and has the advantages of novel and efficient synthesis method, mild reaction conditions, no pollution, high yield of the product and suitability for industrialized production.
The trifluoromethyl-bisisothiazolinone-difluoromethoxy pyrazole compound synthesized by the invention contains trifluoromethyl-difluoromethoxy pyrazole and active structures of bisbenzisothiazolinone, has good inhibition effects on fungi such as candida albicans, candida tropicalis, trichoderma viride, trichoderma atroviride, rhizoctonia solani and the like, wherein the minimum inhibitory concentration on candida albicans is only 0.78ug/mL, and has excellent antifungal biological activity.
Detailed Description
The invention will be further illustrated by the following examples, which are not intended to limit the scope of the invention, in order to facilitate the understanding of those skilled in the art. The technical means used in the examples are conventional means well known to those skilled in the art unless otherwise indicated. Unless specifically stated otherwise, the reagents, methods and apparatus employed in the present invention are those conventional in the art.
Example 1
(1) 60mmol of ethyl trifluoroacetoacetate and 60mmol of methyl hydrazine are added into 80mL of ethanol, concentrated hydrochloric acid is added dropwise, reflux is carried out for 48 hours at the temperature of 80 ℃, cooling is carried out, water and ethyl acetate are added, shake extraction is carried out, standing and layering are carried out, an ethyl acetate organic phase is concentrated, and drying is carried out, thus obtaining a 1-methyl-3-trifluoromethyl-5-hydroxy-pyrazole intermediate; the structure is thatThe actual yield was 8.63g, 86.6%.
(2) Adding 120mmol of 1-methyl-3-trifluoromethyl-5-hydroxy-pyrazole intermediate into 50mL of potassium hydroxide solution with the mass fraction of 25%, dropwise adding 13mL of formaldehyde water solution with the mass fraction of 37%, stirring for reacting for 2H, then adding 80mL of 25% potassium hydroxide solution and 150mL of acetonitrile, introducing chlorodifluoromethane, continuing to react for 2H, adding hydrochloric acid solution for neutralization, adding ethyl acetate, oscillating for extraction, standing for layering, concentrating an ethyl acetate organic phase, and drying to obtain the 1-methyl-3-trifluoromethyl-4-hydroxymethyl-5-difluoromethoxy-1-H-pyrazole intermediate with the structural formula ofThe actual yield was 24.91g, 78.6%.
(3) 100mmol of 1-methyl-3-trifluoromethyl-4-hydroxymethyl-5-difluoromethoxy-1-H-pyrazole was added to 150mL of thionyl chloride, the mixture was reacted at room temperature for 2 hours, concentrated under reduced pressure, washed with diethyl ether and dried to obtain 1-methyl-3-trifluoromethyl-4-chloromethyl-5-difluoromethoxy-1-H-pyrazole intermediate; the structure is thatThe actual yield was 21.54g, 81.6%. The reaction route is as follows:
example 2
100mmol of 1-methyl-3-trifluoromethyl-4-chloromethyl-5-difluoromethoxy-1-H-pyrazole and 80mol of iminodiacetic acid are added into 400mL of tetrahydrofuran, 30mL of 15% sodium hydroxide aqueous solution with mass fraction is dropwise added into the mixture for reaction at 40 ℃ for 3H, the tetrahydrofuran is concentrated and removed after the reaction, hydrochloric acid solution is dropwise added to the mixture under the condition of pH to 4, ethyl acetate is added, the mixture is subjected to oscillation extraction, standing and layering, and an ethyl acetate organic phase is concentrated and dried to obtain a trifluoromethyl-bis (diacetic acid amine) -difluoromethoxy pyrazole intermediate. The reaction route is as follows:
example 3
This example differs from example 2 in that iminodiacetic acid was used in an amount of 120mmol.
Example 4
This example differs from example 2 in that iminodiacetic acid was used in an amount of 140mmol.
Example 5
This example differs from example 3 in that the mass fraction of the aqueous sodium hydroxide solution is 30%.
Example 6
This example differs from example 3 in that the mass fraction of the aqueous sodium hydroxide solution is 40%.
Example 7
This example differs from example 5 in that the reaction temperature is 60 ℃.
Example 8
This example differs from example 5 in that the reaction temperature is 70 ℃.
Example 9
This example differs from example 7 in that the reaction time is 8h.
Example 10
This example differs from example 7 in that the reaction time is 12h.
n1 is the molar amount of 1-methyl-3-trifluoromethyl-4-chloromethyl-5-difluoromethoxy-1-H-pyrazole.
n2 is the molar amount of iminodiacetic acid.
C is the mass fraction of the aqueous sodium hydroxide solution.
T is the reaction temperature.
t is the reaction time.
Example 11
Adding 100mmol of trifluoromethyl-bis (diacetic acid amine) -difluoromethoxy pyrazole intermediate and 150-300mmol of hydroxyethyl benzisothiazolinone into methylene dichloride, stirring and dissolving, adding 120mmol of 1- (3-dimethylaminopropyl) -3-ethyl carbodiimide hydrochloride (EDCl) and 120mmol of 1-Hydroxybenzotriazole (HOBT), reacting for 4 hours at 15 ℃, concentrating and removing methylene dichloride, separating and purifying the crude product by silica gel column chromatography, and eluting with the volume ratio V (ethyl acetate): V (petroleum ether) =1:9 to obtain the trifluoromethyl-bis (isothiazolinone-difluoromethoxy pyrazole compound. The reaction route is as follows:
example 12
This example differs from example 11 in that the amount of hydroxyethyl benzisothiazolinone used is 220mmol.
Example 13
This example differs from example 11 in that the amount of hydroxyethyl benzisothiazolinone used is 300mmol.
Example 14
This example differs from example 12 in that the reaction temperature is 30 ℃.
Example 15
This example differs from example 12 in that the reaction temperature is 40 ℃.
Example 16
This example differs from example 14 in that the reaction time is 12h.
Example 17
This example differs from example 14 in that the reaction time is 18h.
n1 is the molar amount of trifluoromethyl-bis (diacetamine) -difluoromethoxypyrazole intermediate.
n2 is the molar amount of hydroxyethyl benzisothiazolinone.
T is the reaction temperature.
t is the reaction time.
In vitro antifungal experiments:
respectively taking candida albicans, candida tropicalis, trichoderma viride, trichoderma atroviride, and rhizoctonia solani as experimental strains, and culturing at the constant temperature of 28 ℃ for 30 days.
Performing antifungal experiment by double dilution method, adding trifluoromethyl-bis-isothiazolinone-difluoromethoxy pyrazole compound synthesized in example 17 into dimethyl sulfoxide, diluting with sterile water to obtain compound solutions with mass concentration of 0.39-100ug/mL, removing 0.5mL of compound solution, adding into agar culture medium containing culture dish, and inoculating 1×10 of compound solution 6 CFU/mL experimental strain is cultured for 48 hours at 28 ℃, fungus growth condition is observed, and no antibacterial effect and no fungus growth are caused when the fungus growsThen there is a bacteriostatic effect and the minimum inhibitory concentration of the compound solution is tested.
| Minimum inhibitory concentration (ug/mL) | |
| Candida albicans | 0.78 |
| Candida tropicalis | 1.56 |
| Trichophyton mentagrophytes | 50 |
| Trichoderma viride | 12.5 |
| Rhizoctonia solani of rice | 12.5 |
The above embodiments are preferred embodiments of the present invention, and besides, the present invention may be implemented in other ways, and any obvious substitution is within the scope of the present invention without departing from the concept of the present invention.
Claims (7)
1. The synthesis method of the trifluoromethyl-bis-isothiazolinone-difluoromethoxy pyrazole compound is characterized in that the structural formula of the trifluoromethyl-bis-isothiazolinone-difluoromethoxy pyrazole compound is as follows:
the synthesis method comprises the following steps:
s1, adding 1-methyl-3-trifluoromethyl-4-chloromethyl-5-difluoromethoxy-1-H-pyrazole and iminodiacetic acid into tetrahydrofuran, stirring, dissolving, dropwise adding aqueous solution of sodium hydroxide, concentrating after reaction to remove tetrahydrofuran, dropwise adding hydrochloric acid solution to pH 4-5, adding ethyl acetate, and extracting to obtain trifluoromethyl-bis (diacetic acid amine) -difluoromethoxy pyrazole intermediate; the structure is that
S2, adding trifluoromethyl-bis (diacetic acid amine) -difluoromethoxy pyrazole intermediate into dichloromethane, wherein the structural formula isAfter stirring and dissolving, adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole, concentrating after reaction, and separating and purifying the crude product by silica gel column chromatography to obtain the trifluoromethyl-bisisothiazolinone-difluoromethoxy pyrazole compound.
2. The method for synthesizing a trifluoromethyl-bis-isothiazolinone-difluoromethoxy pyrazole compound according to claim 1, wherein the molar ratio of 1-methyl-3-trifluoromethyl-4-chloromethyl-5-difluoromethoxy-1-H-pyrazole and iminodiacetic acid in S1 is 1:0.8-1.4.
3. The method for synthesizing a trifluoromethyl-bis-isothiazolinone-difluoromethoxy pyrazole compound according to claim 1, wherein the mass fraction of the aqueous solution of sodium hydroxide in S1 is 15-40%.
4. The method for synthesizing a trifluoromethyl-bis-isothiazolinone-difluoromethoxy pyrazole compound according to claim 1, wherein the reaction in S1 is carried out at a temperature of 40 to 70 ℃ for 3 to 12 hours.
5. The method for synthesizing a trifluoromethyl-bis-isothiazolinone-difluoromethoxy pyrazole compound according to claim 1, wherein the molar ratio of trifluoromethyl-bis (diacetic acid amine) -difluoromethoxy pyrazole intermediate to hydroxyethyl benzisothiazolinone in S2 is 1:1.5-3.
6. The method for synthesizing a trifluoromethyl-bis-isothiazolinone-difluoromethoxy pyrazole compound according to claim 1, wherein the reaction in S2 is carried out at 15-40 ℃ for 4-18h.
7. The method for synthesizing a trifluoromethyl-bis-isothiazolinone-difluoromethoxy pyrazole compound according to claim 1, wherein the method for synthesizing 1-methyl-3-trifluoromethyl-4-chloromethyl-5-difluoromethoxy-1-H-pyrazole is as follows:
(1) Adding ethyl trifluoroacetoacetate and methyl hydrazine into ethanol, dropwise adding concentrated hydrochloric acid, refluxing at 70-85 ℃ for 36-48h, cooling, adding water and ethyl acetate, and extracting to obtain a 1-methyl-3-trifluoromethyl-5-hydroxy-pyrazole intermediate; the structure is that
(2) Adding a 1-methyl-3-trifluoromethyl-5-hydroxy-pyrazole intermediate into a potassium hydroxide solution with the mass fraction of 20-30%, dropwise adding a formaldehyde aqueous solution with the mass fraction of 37%, stirring for reacting for 1-2H, then adding a potassium hydroxide solution with the mass fraction of 20-30% and acetonitrile, introducing chlorodifluoromethane, continuing to react for 2-3H, adding a hydrochloric acid solution for neutralization, adding ethyl acetate, extracting to obtain the 1-methyl-3-trifluoromethyl-4-hydroxymethyl-5-difluoromethoxy-1-H-pyrazole intermediate with the structural formula of
(3) Adding 1-methyl-3-trifluoromethyl-4-hydroxymethyl-5-difluoromethoxy-1-H-pyrazole into thionyl chloride, reacting for 1-3H at room temperature, concentrating under reduced pressure, washing, and drying to obtain a 1-methyl-3-trifluoromethyl-4-chloromethyl-5-difluoromethoxy-1-H-pyrazole intermediate; the structure is that
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9500693D0 (en) * | 1994-01-17 | 1995-03-08 | Sandoz Ltd | Disperse dyes |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9500693D0 (en) * | 1994-01-17 | 1995-03-08 | Sandoz Ltd | Disperse dyes |
Non-Patent Citations (2)
| Title |
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