CN107674027B - 13C-marked pyraoxystrobin and synthetic method thereof - Google Patents
13C-marked pyraoxystrobin and synthetic method thereof Download PDFInfo
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- CN107674027B CN107674027B CN201711018789.3A CN201711018789A CN107674027B CN 107674027 B CN107674027 B CN 107674027B CN 201711018789 A CN201711018789 A CN 201711018789A CN 107674027 B CN107674027 B CN 107674027B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/18—One oxygen or sulfur atom
- C07D231/20—One oxygen atom attached in position 3 or 5
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/002—Heterocyclic compounds
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N1/00—Sampling; Preparing specimens for investigation
- G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
Abstract
The invention provides a13The invention provides C-labeled pyraoxystrobin and a synthesis method thereof, relates to the technical field of stable isotope labeling synthesis, and provides13The synthesis method of the C-marked pyraoxystrobin comprises the steps of using chlorobenzene as a raw material, and obtaining a first product through acylation reaction and condensation ring-closing reaction; carrying out condensation reaction, methylation reaction and reaction with a bromination reagent on methyl o-methylacetate to obtain a second product; reacting the first product with the second product in an alkaline environment to obtain13C-labeled pyraoxystrobin. The synthetic method provided by the invention has the advantages of simple operation process and high utilization rate of stable isotope atoms, and is synthesized by the synthetic method provided by the invention13The C-labeled pyraoxystrobin is easy to separate and purify, the chemical purity of the product is more than 98%, and the isotopic abundance is more than 98%.
Description
Technical Field
The invention relates to the technical field of stable isotope labeling synthesis, in particular to a stable isotope labeling synthetic method13C-marked pyraoxystrobin and a synthesis method thereof.
Background
Pyraoxystrobin (pyraoxystrobin) with chemical name of (E) -2- [2- [ [3- (4-chlorophenyl) -1-methyl-1H-pyrazole-5-oxyl]Methyl radical]Phenyl radical]-methyl 3-methoxyacrylate, chemical name (E) -2- [ [ [3- (4-chlorophenylyl) -1-methyl-1H-pyrazol-5-yl)]oxy]methyl]- α - (methoxy methyl) -methyl ester, molecular formula C22H21ClN2O4CAS registry number 862588-11-2.
Pyraoxystrobin belongs to methoxy acrylate bactericides and is created and developed by Shenyang chemical research institute. The medicine is a respiratory inhibitor of fungus mitochondria, and the action mechanism of the medicine is that the electronic transmission between cytochrome b and cl is locked, the energy synthesis of cells is prevented, and the respiration of mitochondria is inhibited to achieve the bactericidal action. Pyraoxystrobin can inhibit hyphal growth and spore germination, has good inhibition effect on pathogenic bacteria of deuteromycotina, flagellata and ascomycotina, and has obvious protection and treatment effects on powdery mildew and downy mildew of cucumber.
In recent years, LC-MS has the characteristics of accuracy, high efficiency, sensitivity and the like, is widely applied to measuring pesticide residue detection, and can eliminate the recovery rate difference caused by the pretreatment process of a sample in chemistry or physics by adopting an Isotope Dilution Mass Spectrometry (IDMS) and measuring the ion ratio of corresponding mass number and comparing the ion ratio with the standard ratio, thereby obviously improving the stability of the detection method. The development of stable isotope labeled pyraoxystrobin not only accurately provides a standard reagent for quantitatively detecting pyraoxystrobin, but also can effectively serve for researching the migration and residue of pyraoxystrobin in plants, the digestion, metabolic pathways and action mechanisms in soil and environmental behaviors.
The existing synthetic research literature of stable isotope labeled pyraoxystrobin is fresh, and Liu Chong and Dingxing (chemical bulletin, 2011, Vol.69, No.12,1445-1449) reports14C-marked chlorobenzoic acid is taken as a raw material and synthesized by three steps of condensation, cyclization and substitution14And C is marked on pyraoxystrobin on the pyrazole ring. But using radioactivity14The C-labeled raw material is synthesized, has high requirements on experimental operating conditions, is only suitable for trace research and is not suitable for batch production. The pyraoxystrobin with natural abundance, namely plum 281569, Liuchang (J.Agric. Food chem.2010,58,2664-2667, CN1657524 and WO2005080344A1) is prepared by using chloroacetophenone as a raw material, and performing condensation, ring closure, substitution, esterification, methylation and other steps, so that the reaction temperature is high, impurities in a reaction system are more, the yield is low, and the post-treatment is complex and the purification difficulty is high.
Therefore, it is important to develop a method for synthesizing pyraoxystrobin labeled with stable isotope, which has simple preparation process, high utilization rate of stable isotope atoms and easy separation and purification of products, and has good economical efficiency and use value.
In view of the above, the present invention is particularly proposed.
Disclosure of Invention
The first purpose of the invention is to provide13The method for synthesizing C-labeled pyraoxystrobin is used for solving the technical problems of complex synthesis process, more impurities, low yield, high purification difficulty and incapability of batch production of isotope-labeled pyraoxystrobin in the prior art.
The second purpose of the invention is to provide a method for synthesizing a compound with a plurality of compounds by applying the synthesis method13Pyraoxystrobin at the C-marker site.
The invention provides13A method for synthesizing C-labeled pyraoxystrobin, comprising the steps of:
step (a): chlorobenzene is used as a raw material, and a first product is obtained through acylation reaction and condensation ring-closing reaction;
step (b): carrying out condensation reaction, methylation reaction and reaction with a bromination reagent on methyl o-methylacetate to obtain a second product;
step (c): the first product and the second product react in an alkaline environment to obtain the13C-labeled pyraoxystrobin;
wherein the stable isotope13The C label is introduced by one or more of the acylation reaction in the step (a), the condensation reaction in the step (b) or the methylation reaction.
Further, the acylation reaction in the step (a) comprises an acetylation reaction and a formylation reaction;
the reagent for acetylation reaction is acetyl chloride; the reagent of the formylation reaction is selected from dimethyl carbonate or methyl formate; the reagent of the condensation cyclization reaction is methyl hydrazine;
preferably, the acetylation reaction in step (a) is carried out under catalyst-catalyzed conditions; the temperature of the acetylation reaction is 20-100 ℃, and the time is 4-12 h;
preferably, the acylation is a friedel-crafts acylation;
preferably, the catalyst is aluminum trichloride.
Further, the step (a) comprises the steps of taking chlorobenzene as a raw material, and reacting the chlorobenzene with acetyl chloride to generate parachloroacetophenone; the p-chloroacetophenone reacts with dimethyl carbonate in an alkaline environment to obtain 3- (4-chlorphenyl) -3-carbonyl-methyl propionate; and reacting the 3- (4-chlorphenyl) -3-carbonyl-methyl propionate with methyl hydrazine to obtain the 3- (4-chlorphenyl) -1-methyl-1H-5-pyrazole alcohol.
Further, the molar ratio of the p-chloroacetophenone to the dimethyl carbonate is 1:1-1: 4; the molar ratio of the 3- (4-chlorphenyl) -3-carbonyl-methyl propionate to the methyl hydrazine is 1:1-1: 4;
preferably, the reaction temperature of the p-chloroacetophenone and the dimethyl carbonate is 0-100 ℃, and the reaction time is 4-12 h;
the reaction of the 3- (4-chlorphenyl) -3-carbonyl-methyl propionate and the methyl hydrazine is a ring closing reaction, the temperature of the ring closing reaction is 20-100 ℃, and the time of the ring closing reaction is 4-12 h.
Further, the substance subjected to condensation reaction with methyl o-tolylacetate in the step (b) is selected from methyl formate, ethyl formate, n-propyl formate, isopropyl formate or n-butyl formate;
the methylation reagent for the methylation reaction is selected from dimethyl sulfate, dimethyl carbonate, methyl trifluoromethanesulfonate or methyl iodide;
the brominating reagent is selected from N-bromosuccinimide, bromine, dibromohydantoin or tetrabromocycloketone.
Further, the step (b) comprises the condensation reaction of methyl o-tolylacetate and formate in an alkaline environment to obtain 2- (2' -methyl) phenyl-3-hydroxy methyl acrylate; reacting the 2- (2 '-methyl) phenyl-3-hydroxy methyl acrylate with a methylating agent in an alkaline environment to obtain 2- (2' -methyl) phenyl-3-methoxy methyl acrylate; and reacting the 2- (2 '-methyl) phenyl-3-methoxy methyl acrylate with a bromination reagent to obtain the Z, E configuration 2- (2' -bromomethyl) phenyl-3-methoxy methyl acrylate.
Further, the condensation reaction temperature of the o-methyl phenylacetate and methyl formate is 0-100 ℃, and the condensation reaction time is 4-12 h; the methylation reaction of the 2- (2' -methyl) phenyl-3-hydroxy methyl acrylate and the dimethyl sulfate is carried out at the temperature of 0-100 ℃ for 4-12 h; the reaction of the methyl 2- (2' -methyl) phenyl-3-methoxyacrylate and the N-bromosuccinimide is carried out under the catalysis of a catalyst, the reaction temperature is 0-100 ℃, and the reaction time is 4-12 h;
preferably, the molar ratio of the methyl o-phenylacetate to the methyl formate is 1:1 to 1: 4; the molar ratio of the methyl 2- (2' -methyl) phenyl-3-hydroxyacrylate to the dimethyl sulfate is 1:1-1: 4; the molar ratio of the methyl 2- (2' -methyl) phenyl-3-methoxyacrylate to the N-bromosuccinimide is 1:1-1: 4;
preferably, the catalyst is AIBN or benzoyl peroxide.
Further comprises recrystallizing the Z, E configuration methyl 2- (2 '-bromomethyl) phenyl-3-methoxyacrylate to obtain (E) -methyl 2- (2' -bromomethyl) phenyl-3-methoxyacrylate.
Further, step (c) comprises reacting 3- (4-chlorophenyl) -1-methyl-1H-5-pyrazolol with methyl 2- (2' -bromomethyl) phenyl-3-methoxyacrylate in an alkaline environment to form said13C-labeled pyraoxystrobin.
In addition, the invention also provides a synthetic method obtained by the synthesis method13C-labeled pyraoxystrobin.
The invention provides13The synthesis method of the C-marked pyraoxystrobin comprises the steps of using chlorobenzene as a raw material, and obtaining a first product through acylation reaction and condensation ring-closing reaction; carrying out condensation reaction, methylation reaction and bromine substitution reaction on methyl o-methylacetate to obtain a second product; reacting the first product with the second product in an alkaline environment to obtain13C-labeled pyraoxystrobin. The synthetic method provided by the invention has the advantages of simple operation process and high utilization rate of stable isotope atoms, and is synthesized by the synthetic method provided by the invention13The C-labeled pyraoxystrobin is easy to separate and purify, the chemical purity of the product is more than 98%, and the isotopic abundance is more than 98%.
Drawings
FIG. 1 is a drawing provided in example 7 of the present invention13C3A nuclear magnetic resonance hydrogen spectrum of the labeled pyraoxystrobin;
FIG. 2 is a drawing provided in example 7 of the present invention13A liquid phase mass spectrogram of pyraoxystrobin C;
FIG. 3 is a drawing provided in example 7 of the present invention13C3Liquid phase mass spectrum of pyraoxystrobin.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the accompanying drawings, and it should be understood that the described embodiments are some, but not all embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The invention provides a13The method for synthesizing the C-marked pyraoxystrobin comprises the following steps of:
step (a): chlorobenzene is used as a raw material, and a first product is obtained through acylation reaction and condensation ring-closing reaction;
step (b): carrying out condensation reaction, methylation reaction and bromination reaction on methyl o-methylacetate to obtain a second product;
step (c): the first product and the second product are reacted in an alkaline environment to obtain13C-labeled pyraoxystrobin.
Wherein the stable isotope13The C label is introduced by one or more of the acylation reaction in step (a), condensation reaction in step (b) or methylation reaction, e.g. a single site stable isotope13The C-label may be introduced by an acylation reaction in step (a), or a condensation reaction in step (b), or a methylation reaction in step (b); two site stable isotopes13The C-label may be introduced by an acylation reaction in step (a) and a condensation reaction in step (b), or a condensation reaction in step (b) and a methylation reaction in step (b), or an acylation reaction in step (a) and a methylation reaction in step (b); three site stable isotopes13The C label may be introduced by acylation in step (a) and condensation in step (b) and methylation in step (b).
The synthetic method provided by the invention is simple in operation process and high in utilization rate of stable isotope atoms.
In a preferred embodiment, the acylation reaction in step (a) comprises an acetylation reaction and a formylation reaction;
the acetylation reaction reagent is acetyl chloride; the reagent for the formylation reaction is selected from dimethyl carbonate or methyl formate.
In a preferred embodiment, the acetylation in step (a) is a friedel-crafts acylation; aluminum trichloride is used as a catalyst and is carried out in a sealed tank; the temperature of the acetylation reaction is 20-100 deg.C, and may be, for example, but not limited to, 20 deg.C, 30 deg.C, 40 deg.C, 50 deg.C, 60 deg.C, 70 deg.C, 80 deg.C, 90 deg.C or 100 deg.C; the time of the acylation reaction is 4 to 12 hours, and for example, but not limited to, 4 hours, 6 hours, 8 hours, 10 hours or 12 hours.
In a more preferred embodiment, the temperature of the acetylation reaction is 55 ℃ and the time of the acylation reaction is 6 h.
In a more preferred embodiment, the formylation reagent in step (a) is selected from dimethyl carbonate and the condensed ring reagent is methylhydrazine.
In a preferred embodiment, step (a) comprises reacting chlorobenzene with acetyl chloride to form parachloroacetophenone; p-chloroacetophenone reacts with dimethyl carbonate in an alkaline environment to obtain 3- (4-chlorphenyl) -3-carbonyl-methyl propionate; 3- (4-chlorphenyl) -3-carbonyl-methyl propionate reacts with methyl hydrazine to obtain 3- (4-chlorphenyl) -1-methyl-1H-5-pyrazole alcohol.
When stabilizing isotopes13When the C label is introduced by the acylation reaction in the step (a), the raw material acetyl chloride is selected13C-labeled acetyl chloride.
Wherein, the molar ratio of the p-chloroacetophenone to the dimethyl carbonate is 1:1-1:4, such as but not limited to 1:1, 1:1.1, 1:2, 1:3 or 1: 4; the molar ratio of 3- (4-chlorophenyl) -3-carbonyl-propionic acid methyl ester to methylhydrazine is 1:1 to 1:4, and can be, for example, but not limited to, 1:1, 1:2, 1:3, or 1: 4.
In a more preferred embodiment, the molar ratio of p-chloroacetophenone to dimethyl carbonate is 1:1.1, and the molar ratio of methyl 3- (4-chlorophenyl) -3-carbonyl-propionate to methylhydrazine is 1: 2.
In a preferred embodiment, the temperature of the reaction of p-chloroacetophenone with dimethyl carbonate is 0 to 100 ℃, and for example, but not limited to, 0 ℃, 10 ℃, 20 ℃, 30 ℃, 40 ℃, 50 ℃, 60 ℃, 70 ℃, 80 ℃, 90 ℃ or 100 ℃; the reaction time is 4-12h, for example, but not limited to, 4h, 6h, 8h, 10h or 12 h; the reaction condition of the p-chloroacetophenone and the dimethyl carbonate is an alkaline environment, the adopted base can be, but is not limited to, one or more of sodium ethoxide, potassium tert-butoxide, NaH and NaHMDS, and the used solvent can be one or more of anhydrous DMF, tetrahydrofuran, acetonitrile or dioxane.
In a more preferred embodiment, the reaction temperature of p-chloroacetophenone with dimethyl carbonate is 20 ℃, the reaction time of p-chloroacetophenone with dimethyl carbonate is 6h, and the alkaline environment is NaH in tetrahydrofuran.
In a preferred embodiment, the reaction of 3- (4-chlorophenyl) -3-carbonyl-propionic acid methyl ester with methylhydrazine is a cyclization reaction at a temperature of 20 to 100 ℃, for example, but not limited to, 20 ℃, 30 ℃, 40 ℃, 50 ℃, 60 ℃, 70 ℃, 80 ℃, 90 ℃ or 100 ℃; the time of the ring closing reaction is 4-12h, for example, but not limited to, 4h, 6h, 8h, 10h or 12 h; the solvents used may be: one or more of tetrahydrofuran, methanol, acetonitrile and dioxane.
In a more preferred embodiment, the reaction temperature of 3- (4-chlorophenyl) -3-carbonyl-propionic acid methyl ester with methylhydrazine is 70 ℃, the reaction time of 3- (4-chlorophenyl) -3-carbonyl-propionic acid methyl ester with methylhydrazine is 6h, and the solvent used is tetrahydrofuran.
In a preferred embodiment, the substance undergoing the condensation reaction with methyl o-tolylacetate in step (b) is selected from methyl formate, ethyl formate, n-propyl formate, isopropyl formate or n-butyl formate.
In a more preferred embodiment, the substance undergoing the condensation reaction with methyl o-tolylacetate in step (b) is methyl formate.
In a preferred embodiment, the methylating agent used in the methylation reaction in step (b) is selected from dimethyl sulphate, dimethyl carbonate, methyl triflate or methyl iodide.
In a more preferred embodiment, the methylating agent used in the methylation reaction in step (b) is dimethyl sulphate.
In a preferred embodiment, the brominating reagent for the bromination reaction in step (b) is selected from the group consisting of N-bromosuccinimide, bromine, dibromohydantoin, and tetrabromocycloketone.
In a more preferred embodiment, the brominating reagent for the bromination reaction in step (b) is N-bromosuccinimide.
In a preferred embodiment, step (b) comprises the condensation reaction of methyl o-tolylacetate with methyl formate in an alkaline environment to obtain methyl 2- (2' -methyl) phenyl-3-hydroxyacrylate; reacting 2- (2 '-methyl) phenyl-3-hydroxy methyl acrylate with dimethyl sulfate in an alkaline environment to obtain 2- (2' -methyl) phenyl-3-methoxy methyl acrylate; reacting 2- (2 '-methyl) phenyl-3-methoxy methyl acrylate with N-bromosuccinimide to obtain 2- (2' -bromomethyl) phenyl-3-methoxy methyl acrylate with Z, E configuration.
When stabilizing isotopes13When the C label is introduced by the condensation reaction in the step (b), the raw material methyl formate is selected13C-labeled methyl formate.
When stabilizing isotopes13When the C mark is introduced through the methylation reaction in the step (b), the raw material dimethyl sulfate is selected13C-labelled dimethyl sulphate.
Wherein the condensation reaction temperature of methyl o-tolylacetate and methyl formate is 0-100 deg.C, such as but not limited to 0 deg.C, 10 deg.C, 20 deg.C, 30 deg.C, 40 deg.C, 50 deg.C, 60 deg.C, 70 deg.C, 80 deg.C, 90 deg.C or 100 deg.C; the condensation reaction time is 4-12h, for example, but not limited to, 4h, 6h, 8h, 10h or 12 h; the molar ratio of methyl o-tolylacetate to methyl formate is from 1:1 to 1:4, and may be, for example, but not limited to, 1:1, 1:2, 1:3 or 1: 4; the base used in the alkaline environment can be, but is not limited to, one or more of sodium ethoxide, potassium tert-butoxide, NaH and NaHMDS, and the solvent used can be, but is not limited to, one or more of anhydrous MTBE, DME, tetrahydrofuran, acetonitrile, diethyl ether or dioxane.
In a more preferred embodiment, the condensation reaction temperature of the o-methyl phenylacetate and the methyl formate is 20 ℃, the condensation reaction time is 6h, and the molar ratio of the o-methyl phenylacetate to the methyl formate is 1:2, the alkaline environment is NaH solution in tetrahydrofuran.
In a preferred embodiment, the methylation reaction of methyl 2- (2' -methyl) phenyl-3-hydroxyacrylate with dimethyl sulfate is carried out at a temperature of 0 to 100 ℃, for example, but not limited to, 0 ℃, 10 ℃, 20 ℃, 30 ℃, 40 ℃, 50 ℃, 60 ℃, 70 ℃, 80 ℃, 90 ℃ or 100 ℃; the reaction time is 4-12h, for example, but not limited to, 4h, 6h, 8h, 10h or 12 h; the molar ratio of methyl 2- (2' -methyl) phenyl-3-hydroxyacrylate to dimethyl sulfate is 1:1 to 1:4, and may be, for example, but not limited to, 1:1, 1:2, 1:3 or 1: 4; the alkaline environment may be, for example, but is not limited to NaOH, KOH, K2CO3One or more aqueous solutions thereof.
In a more preferred embodiment, the methylation reaction of methyl 2- (2 '-methyl) phenyl-3-hydroxyacrylate with dimethyl sulfate is carried out at a temperature of 20 ℃ for a reaction time of 4 hours, and the molar ratio of methyl 2- (2' -methyl) phenyl-3-hydroxyacrylate to dimethyl sulfate is 1:2, the alkaline environment is NaOH tetrahydrofuran solution.
In a preferred embodiment, the reaction of methyl 2- (2' -methyl) phenyl-3-methoxyacrylate with N-bromosuccinimide is carried out under the catalysis of a catalyst, wherein the catalyst is AIBN or benzoyl peroxide; the reaction temperature is 0-100 ℃, for example, but not limited to, 0 ℃, 10 ℃, 20 ℃, 30 ℃, 40 ℃, 50 ℃, 60 ℃, 70 ℃, 80 ℃, 90 ℃ or 100 ℃; the reaction time is 4-12h, for example, but not limited to, 4h, 6h, 8h, 10h or 12 h; the molar ratio of methyl 2- (2' -methyl) phenyl-3-methoxyacrylate to N-bromosuccinimide is from 1:1 to 1:4, and may be, for example, but not limited to, 1:1, 1:1.1, 1:2, 1:3, or 1: 4.
In a more preferred embodiment, methyl 2- (2' -methyl) phenyl-3-methoxyacrylate is present in CCl4Reacting with N-bromosuccinimide at 85 deg.C for 6h with AIBN as catalyst, and reacting for 6hThe molar ratio of methyl methacrylate to N-bromosuccinimide is 1: 1.1.
In a preferred embodiment, step (b) further comprises recrystallizing the methyl 2- (2 '-bromomethyl) phenyl-3-methoxyacrylate in the Z, E configuration to obtain methyl (E) -2- (2' -bromomethyl) phenyl-3-methoxyacrylate.
Wherein, the (E) type product can be crystallized and purified by one or more of methanol, ethanol, acetone, DME and diethyl ether.
In a more preferred embodiment, the form (E) product is purified by acetone crystallization.
In a preferred embodiment, step (c) comprises reacting 3- (4-chlorophenyl) -1-methyl-1H-5-pyrazolol with methyl 2- (2' -bromomethyl) phenyl-3-methoxyacrylate in an alkaline environment to form13C-labeled pyraoxystrobin.
Wherein the alkaline environment is a mixed solution of NaH and DMF, C2H5Mixed solution of ONa and DMF, K2CO3Mixed solution with DMF or Cs2CO3Mixed solution with DMF.
The invention uses13The chlorobenzene marked by C is used as a raw material, other raw materials used in the reaction process are common chemical raw materials, and the reaction has simple and convenient operation steps and high yield, so that the method route is suitable for pilot-scale large-batch preparation13C-labeled pyraoxystrobin.
The overall reaction flow is as follows:
according to13C1A, b, c, wherein a is 13, b is 12, and c is 12; 12 for a, 13 for b, 12 for c; 12 for a, 12 for b, 13 for c;
according to13C2A, b, c, wherein a is 13, b is 12, and c is 13; 13 for a, 13 for b, 12 for c; 12 for a, 13 for b, 13 for c;
according to13C3The symbols are a, b and c, respectively, are 13, 13 and 13.
The invention also provides a synthetic method of the synthetic method13C-labeled pyraoxystrobin, which has the following structural formula:
according to13C1A, b, c, wherein a is 13, b is 12, and c is 12; 12 for a, 13 for b, 12 for c; 12 for a, 12 for b, 13 for c;
according to13C2A, b, c, wherein a is 13, b is 12, and c is 13; 13 for a, 13 for b, 12 for c; 12 for a, 13 for b, 13 for c;
according to13C3The symbols are a, b and c, respectively, are 13, 13 and 13.
In order to facilitate a clearer understanding of the present invention, the technical solution of the present invention will be further described below with reference to examples and comparative examples.
Example 1
The embodiment provides a13The preparation method of the C-labeled pyraoxystrobin comprises the following steps:
(1) preparation of 3- (4-chlorophenyl) -1-methyl-1H-5-pyrazolol (I-5)
Under nitrogen, aluminum trichloride (5.10g, 7.58mmol) and chlorobenzene (7.0mL, 69.40mmol) were charged into a 150mL stuffer can and added via syringe at room temperature13C-labelled acetyl chloride (5.0 g, 62.89mmol) was post-blocked and stirred at 55 ℃ for 6 h. After cooling, the reaction was quenched in ice water, extracted, and concentrated to give p-chloroacetophenone as a pale yellow oil (8.90g, 82.40% yield). A nitrogen blanketed three-necked flask was charged with a solution of p-chloroacetophenone (5.26g, 33.72mmol) in tetrahydrofuran (50mL), stirred while adding NaHMDS (2M in THF, 25.3mL, 50.58mmol) under ice salt bath for 0.5h, then added dimethyl carbonate (3.1mL, 37.09mmol), and the mixture was stirred at room temperature for an additional 6 h. The reaction solution was quenched in 6M dilute hydrochloric acid, extracted, concentrated and subjected to column chromatography to give methyl 3- (4-chlorophenyl) -3-carbonylpropionate (5.17g, yield 71.8%) as an orange oil. Adding methyl 3- (4-chlorophenyl) -3-carbonylpropionate (4.8g, 22.48mmol) to a solutionAnhydrous tetrahydrofuran (40mL) solution was added to the closed pot, and after adding methyl hydrazine (40%, 3.9mL, 33.72mmol) and sealing, the reaction solution was concentrated by TLC at 70 ℃ for 6h, indicating completion of the reaction. The residues dissolved in acetone were combined after multiple recrystallizations to give 3- (4-chlorophenyl) -1-methyl-1H-5-pyrazolol as a white powder (2.35g, 49.9% yield).
(2) Preparation of (E) -methyl 2- (2' -bromomethyl) phenyl-3-methoxyacrylate (II-6)
A solution of ethyl methyl o-benzoate (5.00g, 30.45mmol) in dry DME (40.0mL) under nitrogen (5.00g, 30.45mmol) was ice-cooled and NaH (60%, 1.85g, 46.30mmol) was added, stirring was continued for 0.5h and methyl formate (3.72g, 60.9mmol) was added dropwise over 15min (internal temperature below 20 ℃ C.). After the addition was complete, the reaction was stirred at room temperature for 6 h. The reaction was quenched with ice water, acidified with 6M diluted hydrochloric acid to pH 4 of the aqueous layer, extracted, dried, and concentrated to give methyl 2- (2' -methyl) phenyl-3-hydroxyacrylate as a colorless oil (5.00g, yield 85.04%). A mixture of methyl 2- (2' -methyl) phenyl-3-hydroxyacrylate (3.70g, 19.20mmol) and dimethyl sulfate (5.10g, 40.30mmol) was dissolved in ice in tetrahydrofuran and stirred, and aqueous NaOH solution (1.84g/13.4mL) was added dropwise. After the addition, the reaction mixture was stirred at room temperature for 4 hours. Extraction with MTBE, acidification of the aqueous layer and extraction with MTBE. The combined organic layers were washed with water, dried, concentrated, and the crude product was purified by column chromatography to give methyl 2- (2' -methyl) phenyl-3-methoxyacrylate (3.10g, 77.88% yield) as a colorless oil. Methyl 2- (2' -methyl) phenyl-3-methoxyacrylate (2.90g, 13.86mmol), NBS (2.80g, 15.7mmol) and AIBN (0.15g, 0.91mmol), carbon tetrachloride (20mL) were added separately to a closed can, purged with nitrogen, and then closed. The mixture was gradually heated to 85 ℃ and stirred for 6 h. After cooling to room temperature, the mixture was concentrated and purified by column chromatography to give methyl 2- (2' -bromomethyl) phenyl-3-methoxyacrylate (2.9g) in Z, E configuration. The product was dissolved in acetone and crystallized to obtain methyl (E) -2- (2' -bromomethyl) phenyl-3-methoxyacrylate as white crystals (1.8g, yield 47.0%).
(3) Synthesis of (E) -2- {2- [ (3- (4-chlorophenyl) -1-methyl-1H-pyrazol-5-yloxy) methyl ] } -3-methoxy methyl acrylate
To a stirring solution of 3- (4-chlorophenyl) -1-methyl-1H-5-pyrazolol (1.17g, 5.6mmol) in anhydrous DMF (10mL) was added methyl (E) -2- (2' -bromomethyl) phenyl-3-methoxyacrylate (1.6g, 5.6mmol) and Cs2CO3(15.60g, 8.20mmol), raised to 100 ℃ and stirred for 6h, followed by TLC until the reaction is complete. Quenching the reaction liquid into ice water, extracting, concentrating, and purifying by column chromatography to obtain light yellow powder13C-labeled pyraoxystrobin (1.60g, 70.4% yield, 98.4% purity).
Example 2
13The preparation method of the C-labeled pyraoxystrobin comprises the following steps:
(1) preparation of 3- (4-chlorophenyl) -1-methyl-1H-5-pyrazolol (I-5)
Aluminum trichloride (5.10g, 7.58mmol) and chlorobenzene (7.0mL, 69.4mmol) were charged to a 150mL stuffer can under nitrogen, acetyl chloride (5.00g, 62.89mmol) was added via syringe at room temperature and blocked, and stirred at 55 ℃ for 6 h. After cooling, the reaction was quenched in ice water, extracted, and concentrated to give p-chloroacetophenone as a pale yellow oil (8.9g, yield 82.4%). A nitrogen blanketed three-necked flask was charged with NaH (60%, 2.72g, 68.12mmol), tetrahydrofuran (50mL) and dimethyl carbonate (3.1mL, 37.09mmol), respectively. The mixture was heated to reflux and stirred for 30min, then a solution of p-chloroacetophenone (5.26g, 33.72mmol) in tetrahydrofuran was added, the dropwise addition was completed within 15min, stirring was continued for 6h and then cooling was carried out. The reaction solution was quenched in 6M dilute hydrochloric acid, extracted, concentrated and subjected to column chromatography to give methyl 3- (4-chlorophenyl) -3-carbonylpropionate (5.21g, yield 72.4%) as an orange oil. A solution of methyl 3- (4-chlorophenyl) -3-carbonylpropionate (4.8g, 22.48mmol) in dry methanol (40mL) was added to a closed pot, followed by addition of methylhydrazine (40%, 3.9mL, 33.72mmol) and sealing, heating at 70 ℃ and stirring for 6h, TLC showed completion of the reaction, and the reaction was concentrated. The residues dissolved in acetone were combined after multiple recrystallizations to give 3- (4-chlorophenyl) -1-methyl-1H-5-pyrazolol as a white powder (2.35g, 49.9% yield).
(2) Preparation of (E) -methyl 2- (2' -bromomethyl) phenyl-3-methoxyacrylate (II-6)
Nitrogen-protected o-methyl phenylacetic acid methyl ester(5.00g, 30.45mmol) in dry ether (40mL) was added NaH (60%, 1.85g, 46.30mmol) under ice-bath, stirred for 0.5h under ice-bath,13c-labeled methyl formate (3.72g, 60.9mmol) was added dropwise over 15 minutes (temperature in the system was less than 20 ℃). After the addition was complete, the reaction was stirred at room temperature for 8 h. The reaction was quenched with ice water, acidified with 6M hydrochloric acid to pH 4 of the aqueous layer, extracted, dried, and concentrated to give methyl 2- (2' -methyl) phenyl-3-hydroxyacrylate (5.00g, yield 85.04%) as a colorless oil. A mixture of methyl 2- (2' -methyl) phenyl-3-hydroxyacrylate (3.70g, 19.2mmol) and dimethyl sulfate (5.10g, 40.30mmol) was stirred under ice bath, aqueous KOH (2.57g/13.4mL) was added dropwise, and after completion of the addition, the reaction mixture was stirred at room temperature for 4 hours. Extraction with MTBE, acidification of the aqueous layer and extraction with MTBE. The combined organic layers were washed with water, dried, concentrated, and the crude product was purified by column chromatography to give methyl 2- (2' -methyl) phenyl-3-methoxyacrylate (3.10g, 77.88% yield) as a colorless oil. Methyl 2- (2' -methyl) phenyl-3-methoxyacrylate (2.90g, 13.86mmol), NBS (2.80g, 15.70mmol) and dibenzoyl peroxide (0.22g, 0.91mmol), carbon tetrachloride (20mL) were added separately to a closed pot, purged with nitrogen, and then closed. The mixture was gradually heated to 85 ℃ and stirred for 6 h. After cooling to room temperature, the mixture was concentrated and purified by column chromatography to give methyl 2- (2' -bromomethyl) phenyl-3-methoxyacrylate (2.9g) in Z, E configuration. The product was dissolved in acetone and crystallized to obtain methyl (E) -2- (2' -bromomethyl) phenyl-3-methoxyacrylate (1.80g, yield 47.0%).
(3) Synthesis of (E) -2- {2- [ (3- (4-chlorophenyl) -1-methyl-1H-pyrazol-5-yloxy) methyl ] } -3-methoxy methyl acrylate
To 3- (4-chlorophenyl) -1-methyl-1H-5-pyrazolol (1.17g, 5.6mmol) in anhydrous DMF (10mL) under nitrogen was added NaH (60%, 0.28g, 7mmol) and stirred at room temperature for 0.5H, and methyl (E) -2- (2' -bromomethyl) phenyl-3-methoxyacrylate (1.6g, 5.6mmol) was added and stirred at room temperature for 6H, and TLC was followed until the reaction was complete. Quenching the reaction liquid into ice water, extracting, concentrating, and purifying by column chromatography to obtain light yellow powder13C-labeled pyraoxystrobin (1.60g, 70.4% yield, 98.4% purity).
Example 3
13The preparation method of the C-labeled pyraoxystrobin comprises the following steps:
(1) preparation of 3- (4-chlorophenyl) -1-methyl-1H-5-pyrazolol (I-5)
Aluminum trichloride (5.1g, 7.58mmol) and chlorobenzene (7.0mL, 69.4mmol) were charged to a 150mL stuffer can under nitrogen, acetyl chloride (5.00g, 62.89mmol) was added via syringe at room temperature and blocked, and stirred at 55 ℃ for 6 h. After cooling, the reaction was quenched in ice water, extracted, and concentrated to give p-chloroacetophenone as a pale yellow oil (8.9g, yield 82.4%). A nitrogen blanketed three-necked flask was charged with sodium ethoxide (4.63g, 68.12mmol), tetrahydrofuran (50mL) and dimethyl carbonate (3.1mL, 37.09mmol), respectively. The mixture was heated to reflux and stirred for 30min, then a solution of p-chloroacetophenone (5.26g, 33.72mmol) in tetrahydrofuran was added, the addition was completed within 15min, stirring was continued for 6h and then cooling to room temperature. The reaction solution was quenched in 6M dilute hydrochloric acid, extracted, concentrated and subjected to column chromatography to give methyl 3- (4-chlorophenyl) -3-carbonylpropionate (5.09g, yield 70.4%) as an orange oil. A solution of methyl 3- (4-chlorophenyl) -3-carbonylpropionate (4.8g, 22.48mmol) in dry methanol (40mL) was added to a closed pot, followed by addition of methylhydrazine (40%, 3.9mL, 33.72mmol) and sealing, heating at 70 ℃ and stirring for 6h, TLC showed completion of the reaction, and the reaction was concentrated. The residues dissolved in acetone were combined after multiple recrystallizations to give 3- (4-chlorophenyl) -1-methyl-1H-5-pyrazolol as a white powder (2.35g, 49.9% yield).
(2) Preparation of (E) -methyl 2- (2' -bromomethyl) phenyl-3-methoxyacrylate (II-6)
A solution of methyl o-tolylacetate (5.00g, 30.45mmol) in dry MTBE (40mL) under nitrogen blanket was added NaH (60%, 1.85g, 46.30mmol) under ice-bath, stirring was continued for 0.5h, and ethyl formate (5.49g, 60.90mmol) was added dropwise over 15min (temperature in system below 20 ℃). After the addition was complete, the reaction was stirred at room temperature for 6 h. The reaction was quenched with ice water, acidified with 6M diluted hydrochloric acid to pH 4 of the aqueous layer, extracted, dried, and concentrated to give methyl 2- (2' -methyl) phenyl-3-hydroxyacrylate as a colorless oil (5.00g, yield 85.04%). Methyl 2- (2' -methyl) phenyl-3-hydroxyacrylate (3.70g, 19.20mmol) and13c markA mixture of dimethyl sulfate (5.10g, 40.30mmol) was stirred in an ice bath, and aqueous KOH (2.57g/13.4mL) was added dropwise. After the addition, the reaction mixture was stirred at room temperature for 4 hours. Extraction with MTBE, acidification of the aqueous layer and extraction with MTBE. The combined organic layers were washed with water, dried, concentrated and the crude product was purified by column chromatography to give methyl 2- (2' -methyl) phenyl-3-methoxyacrylate (2.90g, 73.20% yield) as a colorless oil. Methyl 2- (2' -methyl) phenyl-3-methoxyacrylate (2.90g, 13.86mmol), NBS (2.8g, 15.70mmol) and dibenzoyl peroxide (0.22g, 0.91mmol), carbon tetrachloride (20mL) were added to the closed can, purged with nitrogen, and then closed. The mixture was gradually heated to 85 ℃ and stirred for 6 h. After cooling to room temperature, the mixture was concentrated and purified by column chromatography to give methyl 2- (2' -bromomethyl) phenyl-3-methoxyacrylate (2.9g) in Z, E configuration. The product was dissolved in acetone and crystallized to obtain methyl (E) -2- (2' -bromomethyl) phenyl-3-methoxyacrylate (1.80g, yield 47.0%).
(3) Synthesis of (E) -2- {2- [ (3- (4-chlorophenyl) -1-methyl-1H-pyrazol-5-yloxy) methyl ] } -3-methoxy methyl acrylate
To a stirring solution of 3- (4-chlorophenyl) -1-methyl-1H-5-pyrazolol (1.17g, 5.60mmol) in anhydrous DMF (10mL) was added methyl (E) -2- (2' -bromomethyl) phenyl-3-methoxyacrylate (1.60g, 5.60mmol) and K2CO3(1.55g, 11.2mmol) and then raised to 100 ℃ and stirred for 6 h. TLC was followed until the reaction was complete. Quenching the reaction liquid into ice water, extracting, concentrating, and purifying by column chromatography to obtain light yellow powder13C-labeled pyraoxystrobin (1.42g, 61.70% yield, 98.4% purity).
Example 4
13The preparation method of pyraoxystrobin with two marked sites comprises the following steps:
(1) preparation of 3- (4-chlorophenyl) -1-methyl-1H-5-pyrazolol (I-5)
Under nitrogen, aluminum trichloride (5.1g, 7.58mmol) and chlorobenzene (7.0mL, 69.40mmol) were charged to a 150mL stuffer can and added via syringe at room temperature13C-labelled acetyl chloride (5.00g, 62.89mmol) was post-blocked and stirred at 55 ℃ for 6 h. After cooling, the reaction solution was quenchedExtraction was performed in ice water, and concentration gave p-chloroacetophenone (8.90g, yield 82.40%) as a pale yellow oil. A nitrogen-blanketed three-necked flask was charged with p-chloroacetophenone (5.26g, 33.72mmol) in tetrahydrofuran and sodium ethoxide (60%, 2.72g, 68.12mmol), heated to reflux and stirred for 0.5h, dimethyl carbonate (3.1mL, 37.09mmol) was added, and the mixture was stirred for 6 h. The reaction solution was quenched in 6M dilute hydrochloric acid, extracted, concentrated and subjected to column chromatography to give methyl 3- (4-chlorophenyl) -3-carbonylpropionate (5.17g, yield 71.5%) as an orange oil. A solution of methyl 3- (4-chlorophenyl) -3-carbonylpropionate (4.8g, 22.48mmol) in tetrahydrofuran (40mL) was added to a closed pot, followed by addition of methylhydrazine (40%, 3.9mL, 33.72mmol) and sealing, heating to 70 ℃ and stirring for 6h, TLC showed completion of the reaction, and the reaction was concentrated. The residues dissolved in acetone were combined after multiple recrystallizations to give 3- (4-chlorophenyl) -1-methyl-1H-5-pyrazolol as a white powder (2.35g, 49.9% yield).
(2) Preparation of (E) -methyl 2- (2' -bromomethyl) phenyl-3-methoxyacrylate (II-6)
N-blanketed methyl o-tolylacetate (5.00g, 30.45mmol) in dry tetrahydrofuran (40mL) was added NaHMDS (2M, 23.1mL, 46.3mmol) in ice and stirring continued for 0.5h,13c-labeled methyl formate (3.72g, 60.90mmol) was added dropwise over 15min (temperature in the system was below 20 ℃). After the addition was complete, the reaction was stirred at room temperature for 6 h. The reaction was quenched with ice water, acidified with 6M diluted hydrochloric acid to pH 4 of the aqueous layer, extracted, dried, and concentrated to give methyl 2- (2' -methyl) phenyl-3-hydroxyacrylate as a colorless oil (5.00g, yield 85.04%). A mixture of methyl 2- (2' -methyl) phenyl-3-hydroxyacrylate (3.70g, 19.20mmol) and dimethyl sulfate (5.10g, 40.30mmol) was stirred under ice bath, and aqueous KOH (2.57g/13.4mL) was added dropwise. After the addition, the reaction mixture was stirred at room temperature for 4 hours. Extraction with MTBE, acidification of the aqueous layer and extraction with MTBE. The combined organic layers were washed with water, dried, concentrated, and the crude product was purified by column chromatography to give methyl 2- (2' -methyl) phenyl-3-methoxyacrylate (3.10g, 77.88% yield) as a colorless oil. Separately, methyl 2- (2' -methyl) phenyl-3-methoxyacrylate (2.90g, 13.86mmol) and NBS (2.8g, 1) were added to the sealed tank5.70mmol) and AIBN (0.15g, 0.91mmol), carbon tetrachloride (20mL), purged with nitrogen and then shut off. The mixture was gradually heated to 85 ℃ and stirred for 6 h. After cooling to room temperature, the mixture was concentrated and purified by column chromatography to give methyl 2- (2' -bromomethyl) phenyl-3-methoxyacrylate (2.9g) in Z, E configuration. The product was dissolved in acetone and crystallized to obtain methyl (E) -2- (2' -bromomethyl) phenyl-3-methoxyacrylate (1.80g, yield 47.0%).
(3) Synthesis of (E) -2- {2- [ (3- (4-chlorophenyl) -1-methyl-1H-pyrazol-5-yloxy) methyl ] } -3-methoxy methyl acrylate
To a stirring solution of 3- (4-chlorophenyl) -1-methyl-1H-5-pyrazolol (1.17g, 5.60mmol) in anhydrous DMF (10mL) under nitrogen, NaH (60%, 0.28g, 7mmol) was added, the mixture was stirred at room temperature for 30min, a solution of methyl (E) -2- (2' -bromomethyl) phenyl-3-methoxyacrylate (1.60g, 5.60mmol) in DMF (2mL) was added, the mixture was stirred at room temperature for 1H, the mixture was raised to 40 ℃ and stirred for 4H, and TLC was performed until the reaction was completed. Quenching the reaction liquid into ice water, extracting, concentrating, and purifying by column chromatography to obtain light yellow powder13C-labeled pyraoxystrobin (1.6g, 70.4% yield, 98.4% purity).
Example 5
13The preparation method of pyraoxystrobin with two marked sites comprises the following steps:
(1) preparation of 3- (4-chlorophenyl) -1-methyl-1H-5-pyrazolol (I-5)
Under nitrogen, aluminum trichloride (5.10g, 7.58mmol) and chlorobenzene (7.0mL, 69.40mmol) were charged into a 150mL stuffer can and added via syringe at room temperature13C-labelled acetyl chloride (5.00g, 62.89mmol) was post-blocked and stirred at 55 ℃ for 6 h. After cooling, the reaction was quenched in ice water, extracted, and concentrated to give p-chloroacetophenone as a pale yellow oil (8.90g, 82.40% yield). A nitrogen blanketed three-necked flask was charged with NaH (60%, 2.72g, 68.12mmol), anhydrous tetrahydrofuran (50mL) and dimethyl carbonate (3.1mL, 37.09mmol), respectively. The mixture was heated to reflux and stirred for 30min, then a solution of p-chloroacetophenone (5.26g, 33.72mmol) in tetrahydrofuran was added, the dropwise addition was completed within 15min, stirring was continued for 6h and then cooling was carried out. Quenching the reaction solution in 6M dilute hydrochloric acid, extracting, concentratingColumn chromatography gave methyl 3- (4-chlorophenyl) -3-carbonylpropionate (5.17g, 71.8% yield) as an orange oil. A solution of methyl 3- (4-chlorophenyl) -3-carbonylpropionate (4.80g, 22.48mmol) in dry methanol (40mL) was added to a closed pot, followed by addition of methylhydrazine (40%, 3.9mL, 33.72mmol) and sealing, heating at 70 ℃ and stirring for 6h, TLC showed completion of the reaction, and the reaction was concentrated. The residues dissolved in acetone were combined after multiple recrystallizations to give 3- (4-chlorophenyl) -1-methyl-1H-5-pyrazolol as a white powder (2.35g, 49.9% yield).
(2) Preparation of (E) -methyl 2- (2' -bromomethyl) phenyl-3-methoxyacrylate (II-6)
A solution of methyl o-tolylacetate (5.00g, 30.45mmol) in dry tetrahydrofuran (40mL) under nitrogen blanket was added NaHMDS (2M, 23.2mL, 46.3mmol) under ice-bath stirring for 0.5h, and ethyl formate (5.48g, 60.90mmol) was added dropwise over 15min (temperature in system below 20 ℃). After the addition was complete, the reaction was stirred at room temperature for 6 h. The reaction was quenched with ice water, acidified with 6M diluted hydrochloric acid to pH 4 of the aqueous layer, extracted, dried, and concentrated to give methyl 2- (2' -methyl) phenyl-3-hydroxyacrylate as a colorless oil (5.00g, yield 85.04%). Methyl 2- (2' -methyl) phenyl-3-hydroxyacrylate (3.70g, 19.20mmol) and13a mixture of C-labeled dimethyl sulfate (5.10g, 40.30mmol) was stirred in an ice bath, and aqueous NaOH (1.84g/13.4mL) was added dropwise. After the addition, the reaction mixture was stirred at room temperature for 4 hours. Extraction with MTBE, acidification of the aqueous layer and extraction with MTBE. The combined organic layers were washed with water, dried, concentrated, and the crude product was purified by column chromatography to give methyl 2- (2' -methyl) phenyl-3-methoxyacrylate (3.10g, 77.88% yield) as a colorless oil. Methyl 2- (2' -methyl) phenyl-3-methoxyacrylate (2.90g, 13.86mmol), NBS (2.80g, 15.70mmol) and AIBN (0.15g, 0.91mmol), carbon tetrachloride (20mL) were added separately to a closed pot, purged with nitrogen, and then closed. The mixture was gradually heated to 85 ℃ and stirred for 6 h. After cooling to room temperature, the mixture was concentrated and purified by column chromatography to give methyl 2- (2' -bromomethyl) phenyl-3-methoxyacrylate (2.90g) in Z/E configuration. The product was dissolved in acetone and crystallized to obtain methyl (E) -2- (2' -bromomethyl) phenyl-3-methoxyacrylate (1.8g, yield 47.0%).
(3) Synthesis of (E) -2- {2- [ (3- (4-chlorophenyl) -1-methyl-1H-pyrazol-5-yloxy) methyl ] } -3-methoxy methyl acrylate
To a stirred solution of 3- (4-chlorophenyl) -1-methyl-1H-5-pyrazolol (1.17g, 5.60mmol) in anhydrous DMF (10mL) under nitrogen was added K2CO3(1.54g, 11.2mmol), methyl (E) -2- (2' -bromomethyl) phenyl-3-methoxyacrylate (1.6g, 5.6mmol) was added, heated to 100 ℃ and stirred for 6h, followed by TLC until the reaction was complete. Quenching the reaction liquid into ice water, extracting, concentrating, and purifying by column chromatography to obtain light yellow powder13C-labeled pyraoxystrobin (1.6g, 70.4% yield, 98.4% purity).
Example 6
13The preparation method of pyraoxystrobin marked with three sites comprises the following steps:
(1) preparation of 3- (4-chlorophenyl) -1-methyl-1H-5-pyrazolol (I-5)
Under nitrogen, aluminum trichloride (5.1g, 7.58mmol) and chlorobenzene (7mL, 69.40mmol) were added to a 150mL stuffer can and added via syringe at room temperature13C-labelled acetyl chloride (5.00g, 62.89mmol) was post-blocked and stirred at 55 ℃ for 6 h. After cooling, the reaction was quenched in ice water, extracted, and concentrated to give p-chloroacetophenone (8.90g, 82.40% yield) as a pale yellow oil. A nitrogen blanketed three-necked flask was charged with NaH (60%, 2.72g, 68.12mmol), tetrahydrofuran (50mL) and dimethyl carbonate (3.1mL, 37.09mmol), respectively, and the mixture was heated to reflux and stirred for 0.5 h. Then, a tetrahydrofuran solution of p-chloroacetophenone (5.26g, 33.72mmol) was added thereto, and the mixture was added dropwise over 15min, followed by stirring for 6 hours. The reaction solution was quenched in 6M dilute hydrochloric acid, extracted, concentrated and subjected to column chromatography to give methyl 3- (4-chlorophenyl) -3-carbonylpropionate (5.17g, yield 71.8%) as an orange oil. A solution of methyl 3- (4-chlorophenyl) -3-carbonylpropionate (4.80g, 22.48mmol) in dry methanol (40mL) was added to a closed pot, followed by addition of methylhydrazine (40%, 3.9mL, 33.72mmol) and sealing, heating at 70 ℃ and stirring for 6h, TLC showed completion of the reaction, and the reaction was concentrated. The residues dissolved in acetone were combined after multiple recrystallizations to give 3- (4-chlorophenyl) -1-methyl-1H-5-pyrazolol (2.35g, product) as a white powderRate 49.9%).
(2) Preparation of (E) -methyl 2- (2' -bromomethyl) phenyl-3-methoxyacrylate (II-6)
A solution of methyl o-tolylacetate (5.00g, 30.45mmol) in dry MTBE (40mL) under nitrogen blanket was added NaH (60%, 1.85g, 46.30mmol) under ice-bath and stirring was continued for 0.5h,13c-labeled methyl formate (3.72g, 60.90mmol) was added dropwise over 15min (temperature in the system was below 20 ℃). After the addition was complete, the reaction was stirred at room temperature for 6 h. The reaction was quenched with ice water, acidified with 6M diluted hydrochloric acid to pH 4 of the aqueous layer, extracted, dried, and concentrated to give methyl 2- (2' -methyl) phenyl-3-hydroxyacrylate as a colorless oil (5.00g, yield 85.04%). Methyl 2- (2' -methyl) phenyl-3-hydroxyacrylate (3.70g, 19.20mmol) and13a mixture of C-labeled dimethyl sulfate (5.10g, 40.30mmol) was stirred in an ice bath, and aqueous NaOH (1.84g/13.4mL) was added dropwise. After the addition, the reaction mixture was stirred at room temperature for 4 hours. Extraction with MTBE, acidification of the aqueous layer and extraction with MTBE. The combined organic layers were washed with water, dried, concentrated, and the crude product was purified by column chromatography to give methyl 2- (2' -methyl) phenyl-3-methoxyacrylate (3.10g, 77.88% yield) as a colorless oil. Methyl 2- (2' -methyl) phenyl-3-methoxyacrylate (2.90g, 13.86mmol), NBS (2.80g, 15.70mmol) and AIBN (0.15g, 0.91mmol), carbon tetrachloride (20mL) were added separately to a closed pot, purged with nitrogen, and then closed. The mixture was gradually heated to 85 ℃ and stirred for 6 h. After cooling to room temperature, the mixture was concentrated and purified by column chromatography to give methyl 2- (2' -bromomethyl) phenyl-3-methoxyacrylate (2.9g) in Z/E configuration. The product was dissolved in acetone and crystallized to obtain methyl (E) -2- (2' -bromomethyl) phenyl-3-methoxyacrylate (1.80g, yield 47.0%).
(3) Synthesis of (E) -2- {2- [ (3- (4-chlorophenyl) -1-methyl-1H-pyrazol-5-yloxy) methyl ] } -3-methoxy methyl acrylate
To a stirring solution of 3- (4-chlorophenyl) -1-methyl-1H-5-pyrazolol (1.17g, 5.60mmol) in anhydrous DMF (10mL) under nitrogen protection was added NaH (60%, 0.28g, 7mmol), and the mixture was stirred at room temperature for 30 min. A solution of methyl (E) -2- (2' -bromomethyl) phenyl-3-methoxyacrylate (1.60g, 5.6mmol) in DMF (2mL) was added, stirred at room temperature for 1h, then brought to 40 deg.CStir for 4h and follow by TLC to the end of the reaction. Quenching the reaction liquid into ice water, extracting, concentrating, and purifying by column chromatography to obtain light yellow powder13C-labeled pyraoxystrobin (1.62g, 70.4% yield, 98.4% purity).
Example 7 qualitative analysis of pyraoxystrobin Structure
Nuclear magnetic analysis:1H NMR(300MHz,CDCl3) δ 7.66-7.61(m,3H),7.55-7.51(m, 1H),7.39-7.36(m,2H),7.34-7.30(m,2H),7.23-7.19(m,1H),5.73(d, J ═ 3.3 Hz,1H),5.03(s,2H),3.83(s,3H),3.71(s,3H),3.69(s, 3H). The results are shown in FIG. 1.
Liquid quality analysis: LCMS (ThermoFinnigan (San Jose, CA) LCQ with ESI) (+) ESI sheath gas flow rate (N)2) 65L/min; auxiliary air flow rate (N)2) 5L/min; the temperature of the heating capillary tube is 250 ℃, and the spraying voltage is 3.3 kV; the capillary voltage was (+ 10V). HPLC Agilent (Palo Alto, CA)1100series system; agilent 1100G1314AUV/Vis detector; the detection wavelength was 254 nm. Chromatographic column, Thermoscientific Hypurity C8(5 um; 2.1x100 mm). Phase A was 0.2% HOAc in water and phase B was 0.2% HOAc in chromatographic methanol. Flow rate 0.25mL/min, gradient a: B95: 5(0min) to 5:95(50min), sample size: 5 uL.
13The mass number of the C pyraoxystrobin is 413.12, and the mass spectrum of the C pyraoxystrobin has an excimer ion peak [ M +1 ]]+414.10, results are shown in fig. 2;13C3the mass number of the pyraoxystrobin is 415.12, and the mass spectrum of the pyraoxystrobin has an excimer ion peak [ M +1 ]]+The results are shown in fig. 3, 415.80.
As can be seen from the results of the above examples, the present invention provides13The synthesis process of C-labeled pyraoxystrobin has simple and effective operation process and post-treatment, high utilization rate of stable isotope atoms, and is synthesized by the synthesis method provided by the invention13The C-labeled pyraoxystrobin is easy to separate and purify, the chemical purity of the product is more than 98%, and the isotopic abundance is more than 98%. And, using the invention provided13The C-labeled pyraoxystrobin can be used as a broad-spectrum bactericide, has good economical efficiency and use value, and can also be used as a standard substance for researching migration and digestion behaviors in the environment.
Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.
Claims (1)
1. Three-site labeling13The preparation method of pyraoxystrobin comprises the following steps:
step (a): chlorobenzene is used as a raw material, and 3- (4-chlorphenyl) -1-methyl-1H-5-pyrazole alcohol is obtained through acylation reaction and condensation cyclization reaction:
under nitrogen, aluminum trichloride (5.1g, 7.58mmol) and chlorobenzene (7mL, 69.40mmol) were added to a 150mL stuffer can and added via syringe at room temperature13C-labeled acetyl chloride (5.00g, 62.89mmol) was post-blocked and stirred at 55 ℃ for 6 h; after cooling, the reaction was quenched in ice water, extracted and concentrated to give p-chloroacetophenone as a pale yellow oil (8.90g, 82.40% yield);
a nitrogen blanketed three-necked flask was charged with NaH (60%, 2.72g, 68.12mmol), tetrahydrofuran (50mL) and dimethyl carbonate (3.1mL, 37.09mmol), respectively, and the mixture was heated to reflux and stirred for 0.5 h; then adding a tetrahydrofuran solution of p-chloroacetophenone (5.26g, 33.72mmol), dropwise adding within 15min, and continuing stirring for 6 h; the reaction was quenched in 6M dilute hydrochloric acid, extracted, concentrated and subjected to column chromatography to give methyl 3- (4-chlorophenyl) -3-carbonylpropionate as an orange oil (5.17g, yield 71.8%);
adding a solution of methyl 3- (4-chlorophenyl) -3-carbonylpropionate (4.80g, 22.48mmol) in dry methanol (40mL) to a closed tank, adding methylhydrazine (40%, 3.9mL, 33.72mmol) and sealing, heating at 70 ℃ and stirring for 6H, TLC showing completion of the reaction, concentrating the reaction solution, and then recrystallizing the residue dissolved in acetone for several times and combining to obtain 3- (4-chlorophenyl) -1-methyl-1H-5-pyrazolol as a white powder (2.35g, 49.9% yield);
step (b): the o-methyl phenylacetate is subjected to condensation reaction, methylation reaction and reaction with a bromination reagent to obtain (E) -2- (2' -bromomethyl) phenyl-3-methoxy methyl acrylate:
a solution of methyl o-tolylacetate (5.00g, 30.45mmol) in dry MTBE (40mL) under nitrogen blanket was added NaH (60%, 1.85g, 46.30mmol) under ice-bath and stirring was continued for 0.5h,13c-labeled methyl formate (3.72g, 60.90mmol) was added dropwise over 15min (the temperature in the system was lower than 20 ℃); after the dropwise addition, stirring the reaction solution at room temperature for 6 hours; the reaction was quenched with ice water, acidified with 6M dilute hydrochloric acid to pH 4 in the aqueous layer, extracted, dried, and concentrated to give methyl 2- (2' -methyl) phenyl-3-hydroxyacrylate as a colorless oil (5.00g, yield 85.04%);
methyl 2- (2' -methyl) phenyl-3-hydroxyacrylate (3.70g, 19.20mmol) and13a mixture of C-labelled dimethyl sulfate (5.10g, 40.30mmol) was stirred in an ice bath and aqueous NaOH (1.84g/13.4mL) was added dropwise; after the dropwise addition, stirring the reaction solution at room temperature for 4 hours; extracting with MTBE, acidifying the water layer, and extracting with MTBE; the combined organic layers were washed with water, dried, concentrated and the crude product was purified by column chromatography to give methyl 2- (2' -methyl) phenyl-3-methoxyacrylate (3.10g, 77.88% yield) as a colorless oil;
separately adding methyl 2- (2' -methyl) phenyl-3-methoxyacrylate (2.90g, 13.86mmol), NBS (2.80g, 15.70mmol) and AIBN (0.15g, 0.91mmol), carbon tetrachloride (20mL) into a closed tank, purging with nitrogen, and then closing; gradually heating the mixture to 85 ℃ and stirring for 6 h; cooling to room temperature, concentrating, and purifying by column chromatography to obtain Z/E configuration methyl 2- (2' -bromomethyl) phenyl-3-methoxyacrylate (2.9 g); the product was crystallized by dissolving in acetone to obtain methyl (E) -2- (2' -bromomethyl) phenyl-3-methoxyacrylate (1.80g, yield 47.0%);
step (c): the 3- (4-chlorphenyl) -1-methyl-1H-5-pyrazole alcohol and (E) -2- (2' -bromomethyl) phenyl-3-methoxy methyl acrylate react in an alkaline environment to obtain (E) -2- {2- [ (3- (4-chlorphenyl) -1-methyl-1H-pyrazol-5-yloxy) methyl]Methyl } 3-methoxyacrylate, i.e. the three sites are labeledRecord13C-labeled pyraoxystrobin;
to a stirring solution of 3- (4-chlorophenyl) -1-methyl-1H-5-pyrazolol (1.17g, 5.60mmol) in anhydrous DMF (10mL) under nitrogen protection was added NaH (60%, 0.28g, 7mmol), and the mixture was stirred at room temperature for 30 min; adding a solution of methyl (E) -2- (2' -bromomethyl) phenyl-3-methoxyacrylate (1.60g, 5.6mmol) in DMF (2mL), stirring at room temperature for 1h, raising the temperature to 40 ℃ and stirring for 4h, and tracking by TLC until the reaction is finished; quenching the reaction liquid into ice water, extracting, concentrating, and purifying by column chromatography to obtain light yellow powder of (E) -2- {2- [ (3- (4-chlorophenyl) -1-methyl-1H-pyrazol-5-yloxy) methyl]Methyl } 3-methoxyacrylate, i.e. labelled with said three sites13C-labeled pyraoxystrobin (1.62g, 70.4% yield, 98.4% purity).
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1869034A (en) * | 2005-05-26 | 2006-11-29 | 沈阳化工研究院 | An arylether kind compound and its preparation and application |
| CN102030710A (en) * | 2010-11-23 | 2011-04-27 | 浙江大学 | Method for synthesizing 14 C-labeled compound of pyraoxystrobin serving as bactericide |
| CN103102308A (en) * | 2011-11-11 | 2013-05-15 | 中国中化股份有限公司 | Method of preparing pyraoxystrobin |
| CN107629004A (en) * | 2017-10-25 | 2018-01-26 | 贾明宏 | 13The pyraoxystrobin and its synthetic method of C flag |
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| CN1869034A (en) * | 2005-05-26 | 2006-11-29 | 沈阳化工研究院 | An arylether kind compound and its preparation and application |
| CN102030710A (en) * | 2010-11-23 | 2011-04-27 | 浙江大学 | Method for synthesizing 14 C-labeled compound of pyraoxystrobin serving as bactericide |
| CN103102308A (en) * | 2011-11-11 | 2013-05-15 | 中国中化股份有限公司 | Method of preparing pyraoxystrobin |
| CN107629004A (en) * | 2017-10-25 | 2018-01-26 | 贾明宏 | 13The pyraoxystrobin and its synthetic method of C flag |
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