CN114436932A - Synthetic process of chlorfenapyr homolog - Google Patents
Synthetic process of chlorfenapyr homolog Download PDFInfo
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- CN114436932A CN114436932A CN202210030434.0A CN202210030434A CN114436932A CN 114436932 A CN114436932 A CN 114436932A CN 202210030434 A CN202210030434 A CN 202210030434A CN 114436932 A CN114436932 A CN 114436932A
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- 238000000034 method Methods 0.000 title claims abstract description 36
- 230000008569 process Effects 0.000 title claims abstract description 35
- CWFOCCVIPCEQCK-UHFFFAOYSA-N chlorfenapyr Chemical compound BrC1=C(C(F)(F)F)N(COCC)C(C=2C=CC(Cl)=CC=2)=C1C#N CWFOCCVIPCEQCK-UHFFFAOYSA-N 0.000 title claims abstract description 34
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 33
- 238000009833 condensation Methods 0.000 claims abstract description 31
- 230000005494 condensation Effects 0.000 claims abstract description 31
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 17
- 238000006114 decarboxylation reaction Methods 0.000 claims abstract description 15
- 239000007858 starting material Substances 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 51
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 42
- FWALJUXKWWBNEO-UHFFFAOYSA-N 2-(4-chloroanilino)acetic acid Chemical compound OC(=O)CNC1=CC=C(Cl)C=C1 FWALJUXKWWBNEO-UHFFFAOYSA-N 0.000 claims description 38
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- 150000001875 compounds Chemical class 0.000 claims description 30
- 239000000463 material Substances 0.000 claims description 26
- 238000010438 heat treatment Methods 0.000 claims description 25
- 238000003756 stirring Methods 0.000 claims description 25
- -1 pyrrole compound Chemical class 0.000 claims description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 20
- 238000006482 condensation reaction Methods 0.000 claims description 17
- 238000004821 distillation Methods 0.000 claims description 16
- 238000001816 cooling Methods 0.000 claims description 15
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 239000000460 chlorine Substances 0.000 claims description 13
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 12
- 229910052801 chlorine Inorganic materials 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 11
- 238000005070 sampling Methods 0.000 claims description 10
- OYUNTGBISCIYPW-UHFFFAOYSA-N 2-chloroprop-2-enenitrile Chemical compound ClC(=C)C#N OYUNTGBISCIYPW-UHFFFAOYSA-N 0.000 claims description 7
- FCYRSDMGOLYDHL-UHFFFAOYSA-N chloromethoxyethane Chemical compound CCOCCl FCYRSDMGOLYDHL-UHFFFAOYSA-N 0.000 claims description 7
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 6
- 238000007259 addition reaction Methods 0.000 claims description 5
- 238000005273 aeration Methods 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 238000000967 suction filtration Methods 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- 238000000643 oven drying Methods 0.000 claims description 4
- 238000004321 preservation Methods 0.000 claims description 4
- 230000002194 synthesizing effect Effects 0.000 claims 4
- 239000000126 substance Substances 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 7
- 238000003786 synthesis reaction Methods 0.000 abstract description 7
- 239000000575 pesticide Substances 0.000 abstract description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 abstract 2
- 239000004471 Glycine Substances 0.000 abstract 1
- 239000007795 chemical reaction product Substances 0.000 description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 239000012467 final product Substances 0.000 description 4
- QSBZRRKSQSAYKF-UHFFFAOYSA-N 4-chloro-2-(4-chlorophenyl)-1-(ethoxymethyl)-5-(trifluoromethyl)pyrrole-3-carbonitrile Chemical compound ClC1=C(C(F)(F)F)N(COCC)C(C=2C=CC(Cl)=CC=2)=C1C#N QSBZRRKSQSAYKF-UHFFFAOYSA-N 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 150000003233 pyrroles Chemical class 0.000 description 3
- 230000000857 drug effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000002351 wastewater Substances 0.000 description 2
- 230000009471 action Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
- C07D207/36—Oxygen or sulfur atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyrrole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a synthesis process of a chlorfenapyr homolog, which relates to the technical field of pesticides and is characterized in that parachlorobenzene glycine is used as a starting material, and the chlorfenapyr homolog is synthesized through cyclization, addition decarboxylation, condensation and chlorination.
Description
Technical Field
The invention relates to the technical field of pesticides, and particularly relates to a synthetic process of a chlorfenapyr homolog.
Background
The chlorfenapyr is a typical representative of pyrrole compounds, the pyrrole compounds, particularly the 2-aryl pyrrole compounds, the chlorfenapyr are novel insecticides developed by taking natural product dioxapyrrolnitrin as a lead, and the action mechanism of the chlorfenapyr is to block the oxidation phosphorylation of mitochondria. Through continuous and intensive research on the synthetic process of the pyrrole compounds, a plurality of new high-activity compounds, in particular to a representative high-activity pyrrole compound chlorfenapyr homologue, the main structural modification or group transformation of which is still the change of groups such as 1-position N-substituent, 2-position aromatic ring and 5-position trifluoromethyl, and the like, and new substituents are introduced, so that a new medicament different from chlorfenapyr can be obtained.
Bromine is needed to be added for bromination reaction in the synthesis process of the chlorfenapyr, the price of the bromine is high, bromine-containing wastewater is easy to generate, and the environmental protection property is poor.
Disclosure of Invention
Aiming at the problems, the invention provides a synthesis process of a chlorfenapyr homolog, which takes p-chlorophenyl glycine as a starting material to synthesize the chlorfenapyr homolog, and the homolog has similar drug effect to chlorfenapyr, low cost, high yield and economic value.
In order to solve the technical problems, the technical scheme of the invention is as follows:
a synthetic process of a chlorfenapyr homolog takes p-chlorophenyl glycine as a starting material, and synthesizes the chlorfenapyr homolog through cyclization, addition decarboxylation, condensation and chlorination, which comprises the following steps:
and (3) cyclization reaction: adding p-chlorophenylglycine, acetonitrile and trifluoroacetic acid into a reaction container, dropwise adding triethylamine under a stirring state, controlling the temperature to be 5-15 ℃, dropwise adding phosphorus trichloride after the dropwise adding is finished, keeping the temperature to be less than 20 ℃ in the dropwise adding process, and keeping the system temperature at 15-25 ℃ for 1.5 hours after the dropwise adding is finished to obtain an intermediate;
addition and decarboxylation reactions: adding 2-chloroacrylonitrile into a reaction container containing the intermediate, cooling the material to a temperature of less than 20 ℃, dropwise adding triethylamine, keeping the temperature at 10-20 ℃ in the dropwise adding process, detecting the pH value of the material after dropwise adding is finished, heating to 55-65 ℃, and keeping the temperature for 2 hours; distilling, removing solvent, washing with water, stirring for 0.5h, vacuum filtering, and oven drying to obtain dried pyrrole compound;
condensation reaction: putting a dried pyrrole compound into a condensation reaction bottle, adding potassium carbonate and ethyl acetate, heating to 45-55 ℃ under stirring, dropwise adding chloromethyl ethyl ether, heating to 50-55 ℃ after dropwise adding, keeping the temperature for 2 hours, sampling, adding water when the content of the pyrrole compound in the material is detected to be less than or equal to 0.5%, stirring for 0.5 hour, standing for layering, taking an ethyl acetate layer, continuously heating, and distilling under normal pressure and reduced pressure to obtain a condensation compound; adding dichloromethane into the condensation compound, stirring and dissolving to obtain a condensation compound dichloromethane solution;
chlorination reaction: cooling the dichloromethane solution of the condensation compound to 10-20 ℃, introducing chlorine into the solution, keeping the temperature at 10-15 ℃ in the aeration process, stopping introducing the chlorine when the content of the condensation compound in the materials is detected to be less than or equal to 0.3% by sampling, and finishing chlorination reaction; and (3) after distillation and desolventizing, adding methanol, heating to 45-55 ℃, keeping the temperature for 0.5h, cooling to 15-25 ℃ after all the materials are dissolved, keeping the temperature for 3h, adjusting the temperature to 15-20 ℃, keeping the temperature, crystallizing, filtering, and drying to obtain the chlorfenapyr homolog chlorine-2- (4-chlorophenyl) -1-ethoxymethyl-5-trifluoromethyl pyrrole-3-nitrile.
Preferably, in the cyclization reaction, the molar ratio of p-chlorophenyl glycine to acetonitrile is 1 (2-4), the molar ratio of p-chlorophenyl glycine to trifluoroacetic acid is 1 (1.05-1.5), the molar ratio of p-chlorophenyl glycine to triethylamine is 1 (1-1.2), the molar ratio of p-chlorophenyl glycine to phosphorus trichloride is 1 (1.02-2), and the residual content of p-chlorophenyl glycine in the intermediate is less than or equal to 0.5%.
Preferably, in the addition decarboxylation reaction, the molar ratio of 2-chloroacrylonitrile to p-chlorophenyl glycine in the cyclization reaction is (1-2): 1, the molar ratio of triethylamine to p-chlorophenyl glycine in the cyclization reaction is (1-1.5): 1, the molar ratio of water to p-chlorophenyl glycine in the cyclization reaction is 3:1, and the content of an intermediate in the material is less than or equal to 1%.
Preferably, in the addition decarboxylation reaction, the distillation is reduced pressure distillation, the negative pressure is-0.09 Mpa, and the temperature is 70 ℃; the pH of the material is = 7.5-8.5.
Preferably, in the condensation reaction, the molar ratio of chloromethyl ethyl ether to p-chlorophenyl glycine in the cyclization reaction is (1-2): 1, the molar ratio of potassium carbonate to p-chlorophenyl glycine in the cyclization reaction is (1-2): 1, the molar ratio of ethyl acetate to p-chlorophenyl glycine in the cyclization reaction is (2-4): 1, and the molar ratio of water to p-chlorophenyl glycine in the cyclization reaction is 2: 1.
Preferably, in the condensation reaction, the atmospheric distillation temperature is 90 ℃, the reduced pressure distillation negative pressure is-0.09 Mpa, and the temperature is 90 ℃.
Preferably, in the chlorination reaction, the molar ratio of chlorine to p-chlorophenyl glycine in the cyclization reaction is (1-1.5): 1, the molar ratio of dichloromethane to p-chlorophenyl glycine in the cyclization reaction is (2-4): 1, and the molar ratio of methanol to p-chlorophenyl glycine in the cyclization reaction is (2-4): 1.
Preferably, in the chlorination reaction, the distillation desolventizing is reduced pressure distillation desolventizing, the negative pressure is-0.06 Mpa, and the temperature is 50 ℃.
After the technical scheme is adopted, the invention has the beneficial effects that:
1) the chlorfenapyr homologue prepared by introducing Cl has similar drug effect to chlorfenapyr, is low in cost, does not generate bromine-containing wastewater, has economic value and is suitable for industrial production.
2) The synthesis process provided by the invention has high yield of intermediate products, the content of the final product chlorfenapyr homolog is more than 99%, and the yield reaches 97.5%.
Detailed Description
The following examples are provided to illustrate the synthesis of a chlorfenapyr homologue according to the present invention, but they should not be construed as limiting the scope of the present invention. In the present invention, all the starting materials for the preparation are commercially available products known to those skilled in the art, unless otherwise specified.
Example 1
And (3) cyclization reaction: adding 0.35mol of p-chlorophenyl glycine, 0.7mol of acetonitrile and 0.37mol of trifluoroacetic acid into a reaction container, dropwise adding 0.385mol of triethylamine under a stirring state, controlling the temperature to be 5 ℃, dropwise adding 0.36mol of phosphorus trichloride after the dropwise adding is finished, keeping the temperature to be less than 20 ℃ in the dropwise adding process, and keeping the system temperature to be 15 ℃ for 1.5 hours after the dropwise adding is finished to obtain an intermediate;
addition and decarboxylation reactions: adding 0.385mol of 2-chloroacrylonitrile into a reaction container containing the intermediate, cooling the material to the temperature of less than 20 ℃, dropwise adding 0.385mol of triethylamine, keeping the temperature at 10 ℃ in the dropwise adding process, detecting the pH value of the material after dropwise adding is finished, heating to 55 ℃, and keeping the temperature for 2 hours; distilling, removing solvent, washing with water, stirring for 0.5h, vacuum filtering, and oven drying to obtain dried pyrrole compound;
condensation reaction: putting a dried pyrrole compound into a condensation reaction bottle, adding 0.35mol of potassium carbonate and 0.7mol of ethyl acetate, heating to 45 ℃ under stirring, dropwise adding 0.35mol of chloromethyl ethyl ether, heating to 50 ℃ after dropwise adding, keeping the temperature for 2 hours, sampling, adding water when the content of the pyrrole compound in the material is detected to be less than or equal to 0.5%, stirring for 0.5 hour, standing for layering, continuously heating an ethyl acetate layer, distilling under normal pressure and reduced pressure to obtain a condensation compound, adding 1.05mol of dichloromethane into the condensation compound, and stirring and dissolving to obtain a dichloromethane solution of the condensation compound;
chlorination reaction: cooling the dichloromethane solution of the condensation compound to 10 ℃, introducing 0.46mol of chlorine into the solution, keeping the temperature at 10 ℃ in the aeration process, stopping introducing the chlorine when the content of the condensation compound in the materials is detected to be less than or equal to 0.3% by sampling, and finishing chlorination reaction; and (3) after distillation and desolventizing, adding 0.7mol of methanol, heating to 45 ℃, preserving heat for 0.5h, cooling to 15 ℃ after complete dissolution, preserving heat for 3h, adjusting the temperature to 15 ℃, performing heat preservation crystallization, suction filtration and drying to obtain the chlorfenapyr homolog chlorine-2- (4-chlorophenyl) -1-ethoxymethyl-5-trifluoromethyl pyrrole-3-nitrile.
In the cyclization reaction product, the intermediate content is 97.3 percent, and the yield is 96.8 percent; in the addition decarboxylation reaction product, the content of the pyrrole compound is 96.4 percent, and the yield is 96.4 percent; in the condensation reaction product, the content of the condensation compound is 96.2 percent, and the yield is 97.1 percent; in the final product, the chlorfenapyr homolog chloro-2- (4-chlorophenyl) -1-ethoxymethyl-5-trifluoromethylpyrrole-3-carbonitrile content was 99%, and the yield was 97.4%.
Example 2
And (3) cyclization reaction: adding 0.35mol of p-chlorophenyl glycine, 0.875mol of acetonitrile and 0.53mol of trifluoroacetic acid into a reaction container, dropwise adding 0.37mol of triethylamine under a stirring state, controlling the temperature to be 10 ℃, dropwise adding 0.42mol of phosphorus trichloride after the dropwise adding is finished, keeping the temperature to be less than 20 ℃ in the dropwise adding process, and keeping the system temperature at 20 ℃ for 1.5 hours after the dropwise adding is finished to obtain an intermediate;
addition and decarboxylation reactions: adding 0.36mol of 2-chloroacrylonitrile into a reaction container containing the intermediate, cooling the material to a temperature of less than 20 ℃, dropwise adding 0.36mol of triethylamine, keeping the temperature at 15 ℃ in the dropwise adding process, detecting the pH value of the material after dropwise adding is finished, heating to 60 ℃, and keeping the temperature for 2 hours; distilling, removing the solvent, adding 1.05mol of water for washing, stirring for 0.5h, performing suction filtration, and drying to obtain a dried pyrrole compound;
condensation reaction: putting a dried pyrrole compound into a condensation reaction bottle, adding 0.39mol of potassium carbonate and 1.05mol of ethyl acetate, heating to 450 ℃ under stirring, dropwise adding 0.36mol of chloromethyl ethyl ether, heating to 53 ℃ after dropwise adding, keeping the temperature for 2 hours, sampling, adding water when the content of the pyrrole compound in the material is detected to be less than or equal to 0.5%, stirring for 0.5 hour, standing for layering, continuously heating an ethyl acetate layer, and distilling under normal pressure and reduced pressure to obtain a condensation compound; adding 0.875mol of dichloromethane into the condensation compound, stirring and dissolving to obtain a condensation compound dichloromethane solution;
chlorination reaction: cooling the dichloromethane solution of the condensation compound to 15 ℃, introducing 0.32mol of chlorine into the solution, keeping the temperature at 13 ℃ in the aeration process, stopping introducing the chlorine when the content of the condensation compound in the materials is detected to be less than or equal to 0.3% by sampling, and finishing chlorination reaction; and (2) after distillation and desolventizing, adding 0.875mol of methanol, heating to 50 ℃, preserving heat for 0.5h, cooling to 15-25 ℃ after all dissolution, preserving heat for 3h, adjusting the temperature to 18 ℃, carrying out heat preservation crystallization, carrying out suction filtration and drying to obtain the chlorfenapyr homolog chlorine-2- (4-chlorphenyl) -1-ethoxymethyl-5-trifluoromethyl pyrrole-3-nitrile.
According to the synthesis process provided by the invention, in the cyclization reaction product, the content of the intermediate is 97.5%, and the yield is 97%; in the addition decarboxylation reaction product, the content of the pyrrole compound is 96.5 percent, and the yield is 96.5 percent; in the condensation reaction product, the content of the condensation compound is 96 percent, and the yield is 97 percent; in the final product, the chlorfenapyr homolog chloro-2- (4-chlorophenyl) -1-ethoxymethyl-5-trifluoromethylpyrrole-3-carbonitrile content was 99%, and the yield was 97.5%.
Example 3
And (3) cyclization reaction: adding 0.35mol of p-chlorophenyl glycine, 0.7mol of acetonitrile and 0.46mol of trifluoroacetic acid into a reaction container, dropwise adding 0.42mol of triethylamine under a stirring state, controlling the temperature at 15 ℃, dropwise adding 0.7mol of phosphorus trichloride after the dropwise adding is finished, keeping the temperature less than 20 ℃ in the dropwise adding process, and keeping the system temperature at 25 ℃ for 1.5 hours after the dropwise adding is finished to obtain an intermediate;
addition and decarboxylation reactions: adding 2-chloroacrylonitrile 0.7mol into a reaction container containing the intermediate, cooling the material to a temperature of less than 20 ℃, dropwise adding triethylamine 0.53mol, keeping the temperature at 20 ℃ in the dropwise adding process, detecting the pH value of the material after dropwise adding is finished, heating to 65 ℃, and keeping the temperature for 2 hours; distilling, removing solvent, washing with water, stirring for 0.5h, vacuum filtering, and oven drying to obtain dried pyrrole compound;
condensation reaction: putting a dried pyrrole compound into a condensation reaction bottle, adding 0.7mol of potassium carbonate and 1.4mol of ethyl acetate, heating to 55 ℃ under stirring, dropwise adding 0.7mol of chloromethyl ethyl ether, heating to 55 ℃ after dropwise adding, keeping the temperature for 2 hours, sampling, adding water when the content of the pyrrole compound in the material is detected to be less than or equal to 0.5%, stirring for 0.5 hour, standing for layering, continuously heating an ethyl acetate layer, and distilling under normal pressure and reduced pressure to obtain a condensation compound; adding 1.4mol of dichloromethane into the condensation compound, stirring and dissolving to obtain a dichloromethane solution of the condensation compound;
chlorination reaction: cooling the dichloromethane solution of the condensation compound to 20 ℃, introducing 0.5mol of chlorine into the solution, keeping the temperature at 15 ℃ in the aeration process, stopping introducing the chlorine when the content of the condensation compound in the materials is detected to be less than or equal to 0.3% by sampling, and finishing chlorination reaction; and after distillation and desolventization, adding 1.4mol of methanol, heating to 55 ℃, preserving heat for 0.5h, cooling to 25 ℃ after complete dissolution, preserving heat for 3h, adjusting the temperature to 20 ℃, carrying out heat preservation crystallization, carrying out suction filtration and drying to obtain the chlorfenapyr homolog chlorine-2- (4-chlorphenyl) -1-ethoxymethyl-5-trifluoromethyl pyrrole-3-nitrile.
According to the synthesis process provided by the invention, in the cyclization reaction product, the content of the intermediate is 97.3%, and the yield is 96.8%; in the addition decarboxylation reaction product, the content of the pyrrole compound is 96.2 percent, and the yield is 96.3 percent; in the condensation reaction product, the content of the condensation compound is 96.1 percent, and the yield is 97 percent; in the final product, the chlorfenapyr homolog chloro-2- (4-chlorophenyl) -1-ethoxymethyl-5-trifluoromethylpyrrole-3-carbonitrile content was 99%, and the yield was 97.4%.
Claims (8)
1. A synthetic process of a chlorfenapyr homolog is characterized in that p-chlorophenyl glycine is used as a starting material, and the chlorfenapyr homolog is synthesized through cyclization, addition decarboxylation, condensation and chlorination, and has a chemical structural formula as follows:
the process of claim 1, wherein the reaction equation is:
the method comprises the following steps:
and (3) cyclization reaction: adding p-chlorophenylglycine, acetonitrile and trifluoroacetic acid into a reaction container, dropwise adding triethylamine under a stirring state, controlling the temperature to be 5-15 ℃, dropwise adding phosphorus trichloride after the dropwise adding is finished, keeping the temperature to be less than 20 ℃ in the dropwise adding process, and keeping the system temperature at 15-25 ℃ for 1.5 hours after the dropwise adding is finished to obtain an intermediate;
addition and decarboxylation reactions: adding 2-chloroacrylonitrile into a reaction container containing the intermediate, cooling the material to a temperature of less than 20 ℃, dropwise adding triethylamine, keeping the temperature at 10-20 ℃ in the dropwise adding process, detecting the pH value of the material after dropwise adding is finished, heating to 55-65 ℃, and keeping the temperature for 2 hours; distilling, removing solvent, washing with water, stirring for 0.5h, vacuum filtering, and oven drying to obtain dried pyrrole compound;
condensation reaction: putting a dried pyrrole compound into a condensation reaction bottle, adding potassium carbonate and ethyl acetate, heating to 45-55 ℃ under stirring, dropwise adding chloromethyl ethyl ether, heating to 50-55 ℃ after dropwise adding, keeping the temperature for 2 hours, sampling, adding water when the content of the pyrrole compound in the material is detected to be less than or equal to 0.5%, stirring for 0.5 hour, standing for layering, taking an ethyl acetate layer, continuously heating, and distilling under normal pressure and reduced pressure to obtain a condensation compound; adding dichloromethane into the condensation compound, stirring and dissolving to obtain a condensation compound dichloromethane solution;
chlorination reaction: cooling the dichloromethane solution of the condensation compound to 10-20 ℃, introducing chlorine into the solution, keeping the temperature at 10-15 ℃ in the aeration process, stopping introducing the chlorine when the content of the condensation compound in the materials is detected to be less than or equal to 0.3% by sampling, and finishing chlorination reaction; and (3) after distillation and desolventizing, adding methanol, heating to 45-55 ℃, preserving heat for 0.5h, cooling to 15-25 ℃ after all the materials are dissolved, preserving heat for 3h, adjusting the temperature to 15-20 ℃, carrying out heat preservation crystallization, carrying out suction filtration and drying to obtain the chlorfenapyr homolog.
2. The process for synthesizing a chlorfenapyr homolog according to claim 2, wherein in the cyclization reaction, the molar ratio of p-chlorophenyl glycine to acetonitrile is 1 (2-4), the molar ratio of p-chlorophenyl glycine to trifluoroacetic acid is 1 (1.05-1.5), the molar ratio of p-chlorophenyl glycine to triethylamine is 1 (1-1.2), the molar ratio of p-chlorophenyl glycine to phosphorus trichloride is 1 (1.02-2), and the residual content of p-chlorophenyl glycine in the intermediate is less than or equal to 0.5%.
3. The process for synthesizing a chlorfenapyr homolog according to claim 2, wherein in the addition decarboxylation reaction, the molar ratio of 2-chloropropene nitrile to p-chlorophenyl glycine in the cyclization reaction is (1-2): 1, the molar ratio of triethylamine to p-chlorophenyl glycine in the cyclization reaction is (1-1.5): 1, the molar ratio of water to p-chlorophenyl glycine in the cyclization reaction is 3:1, and the content of the intermediate in the material is less than or equal to 1%.
4. The process of claim 2, wherein the distillation in the addition decarboxylation reaction is a reduced pressure distillation, the negative pressure is-0.09 Mpa, and the temperature is 70 ℃; the pH of the material is = 7.5-8.5.
5. The process for synthesizing a chlorfenapyr homolog according to claim 2, wherein in the condensation reaction, the molar ratio of chloromethyl ethyl ether to p-chlorophenyl glycine in the cyclization reaction is (1-2): 1, the molar ratio of potassium carbonate to p-chlorophenyl glycine in the cyclization reaction is (1-2): 1, the molar ratio of ethyl acetate to p-chlorophenyl glycine in the cyclization reaction is (2-4): 1, and the molar ratio of water to p-chlorophenyl glycine in the cyclization reaction is 2: 1.
6. The process of claim 2, wherein the condensation reaction is carried out at a distillation temperature of 90 ℃ under atmospheric pressure, at a distillation pressure of-0.09 MPa under reduced pressure, and at a temperature of 90 ℃.
7. The process for synthesizing the chlorfenapyr homolog according to claim 2, wherein in the chlorination reaction, the molar ratio of chlorine to p-chlorophenyl glycine in the cyclization reaction is (1-1.5): 1, the molar ratio of dichloromethane to p-chlorophenyl glycine in the cyclization reaction is (2-4): 1, and the molar ratio of methanol to p-chlorophenyl glycine in the cyclization reaction is (2-4): 1.
8. The process of claim 2, wherein the step of the chlorination reaction comprises the step of distillation and desolventizing under reduced pressure at a pressure of-0.06 MPa and at a temperature of 50 ℃.
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