Preparation method of 2-(2-(bromomethyl) phenyl)-2-(methoxyimino) methyl acetate

Abstract

The invention relates to the technical field of fine chemical engineering, in particular to a preparation method of 2-(2-(bromomethyl) phenyl)-2-(methoxyimino) methyl acetate. The preparation method comprises the following steps: stirring and mixing (E) 2-methoxyimino-[2-(o-methyl) phenyl] methyl acetate and a compound A, and then adding alkali to obtain a mixed solution; wherein the compound A is an aryl compound or a heteroaryl compound of which the structural formula contains at least two fluorine atoms; and adding an initiator, a reducing agent and a catalyst, and reacting to obtain the methyl 2-(2-(bromomethyl) phenyl)-2-(methoxyimino) acetate.

Description

Technical Field

[0001] The present disclosure relates to the field of fine chemical technologies, and particularly relates to a method for preparing methyl 2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetate. Background Art

[0002] Methoxyacrylate fungicides are a new type of fungicides successfully developed with natural product Strobilurins as the active lead compound. Such fungicides have the advantages of broad spectrum, good rainfastness performance, and long effective period. And methyl 2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetate is an important raw material for synthesizing methoxyacrylate fungicides (such as trifloxystrobin and kresoxim-methyl). Currently, there are many methods for synthesizing methyl 2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetate at home and abroad, but all of them require the use of a large amount of raw materials that cause great damage to the environment, such as acids, alkalis, and hydrogen peroxide, and the reaction conditions often require relatively high temperatures; therefore, there is an urgent need for a relatively mild, environmentally friendly, and efficient method for preparing methyl 2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetate. Summary of the Invention

[0003] The present disclosure provides a method for preparing methyl 2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetate to solve the deficiencies in the related technologies.

[0004] According to the first aspect of the embodiments of the present disclosure, a method for preparing methyl 2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetate is provided. The preparation method includes the following steps: Step 1: Add methyl (E)-2-methoxyimino-[2-(o-tolyl)]acetate to an organic solvent to form a first solution, and add compound A to an organic solvent to form a second solution; under stirring, mix the second solution and the first solution, and then add a base to obtain a mixed solution; wherein, the structural formula of compound A contains at least two fluorine atoms.

[0005] Step 2: While keeping the mixed solution obtained in Step 1 under stirring, add an initiator, a reducing agent, and a catalyst, and carry out a reaction to obtain methyl 2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetate.

[0006] In one aspect of the present disclosure, the initiator is selected from benzoyl peroxide and / or azobisisobutyronitrile; preferably, the initiator is selected from azobisisobutyronitrile.

[0007] In one aspect of the present disclosure, based on the total mass of methyl (E)-2-methoxyimino-[2-(o-methyl)phenyl]acetate, the mass percentage content of the initiator is 0.1% - 1.2%; preferably, based on the total mass of methyl (E)-2-methoxyimino-[2-(o-methyl)phenyl]acetate, the mass percentage content of the initiator is 0.1% - 0.5%; specifically, the mass percentage content of the initiator is 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45% or 0.5%; but not limited thereto.

[0008] In one aspect of the present disclosure, the catalyst is selected from palladium catalysts; the palladium catalyst is selected from at least one of dichlorobis(η5-cyclopentadienyl)bis(triphenylphosphine)palladium(II), dichlorobis(triphenylphosphine)palladium(II), palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), palladium on carbon or palladium(III) trifluoroacetate; preferably, the palladium catalyst is selected from dichlorobis(triphenylphosphine)palladium(II).

[0009] In one aspect of the present disclosure, based on the total mass of compound A, the mass percentage content of the palladium catalyst is 0.25% - 0.75%; specifically, the mass percentage content of the palladium catalyst is 0.25%, 0.3%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7% or 0.75%; but not limited thereto.

[0010] In one aspect of the present disclosure, the base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, N,N-diisopropylethylamine or triethylamine; preferably, the base is selected from N,N-diisopropylethylamine.

[0011] In one aspect of the present disclosure, based on the total mass of methyl (E)-2-methoxyimino-[2-(o-methyl)phenyl]acetate, the mass percentage content of N,N-diisopropylethylamine is 0.8% - 2.5%; preferably, based on the total mass of methyl (E)-2-methoxyimino-[2-(o-methyl)phenyl]acetate, the mass percentage content of N,N-diisopropylethylamine is 1.5% - 2.0%; specifically, the mass percentage content of N,N-diisopropylethylamine is 1.5%, 1.55%, 1.6%, 1.65%, 1.7%, 1.75%, 1.8%, 1.85%, 1.9%, 1.95% or 2.0%; but not limited thereto.

[0012] In one aspect of the present disclosure, the reducing agent is selected from metal hydrides, and the metal hydrides are selected from sodium hydride, potassium hydride, calcium hydride, magnesium hydride or barium hydride; preferably, the metal hydride is selected from calcium hydride.

[0013] In one aspect of the present disclosure, based on the total mass of Compound A, the mass percentage of the metal hydride is 1.75% - 2.5%; specifically, the mass percentage of the metal hydride is 1.75%, 1.8%, 1.85%, 1.9%, 1.95%, 2.0%, 2.05%, 2.1%, 2.15%, 2.2% or 2.25%, 2.3%, 2.35%, 2.4%, 2.45% or 2.5%; but not limited thereto.

[0014] In one aspect of the present disclosure, Compound A has the following structural formula:

[0015] Wherein, Ar 1 and Ar 2 are each independently selected from C3-12 cycloalkyl, C6-C12 aryl, 3-12 membered heterocyclic group or 5-12 membered heteroaryl; wherein, the C3-12 cycloalkyl, C6-C12 aryl, 3-12 membered heterocyclic group or 5-12 membered heteroaryl is optionally substituted by one or more C1-C10 alkyl, C2-C10 alkenyl, C1-C10 alkoxy, amino, hydroxy or nitro.

[0016] In one aspect of the present disclosure, Compound A is selected from Compounds A-1 to A-4 having the following structural formulas:

[0017] Wherein, X 1 and X 8 are each independently selected from C, N, O or S; X 2 , X 3 , X 4 , X 5 , X 6 , X 7 are each independently selected from C or N; R 1 and R 2 are each independently selected from hydrogen, C1-C10 alkyl, C2-C10 alkenyl, C1-C10 alkoxy, amino, hydroxy or nitro.

[0018] In one aspect of the present disclosure, Compound A is selected from Compound 4-1-1 to Compound 4-1-3 having the following structural formulas:

[0019] Wherein, R 1 and R 2 are each independently selected from hydrogen, C1-C10 alkyl, C2-C10 alkenyl, C1-C10 alkoxy, amino, hydroxy or nitro.

[0020] In one aspect of the present disclosure, Compound A is selected from the following Compound 1:

[0021] In one aspect of the present disclosure, the organic solvent is selected from dichloroethane, tetrahydrofuran, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, N,N-diethylformamide, N,N-diethylacetamide, cyclohexanone, isophorone or methyl tert-butyl ether; preferably, the organic solvent is selected from N,N-dimethylacetamide.

[0022] According to the second aspect of the embodiments of the present disclosure, methyl 2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetate prepared by the foregoing preparation method is provided.

[0023] According to the third aspect of the embodiments of the present disclosure, the application of the prepared methyl 2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetate in the further preparation of methoxyacrylate fungicides is provided.

[0024] The technical solutions provided by the embodiments of the present disclosure may include the following beneficial effects: As can be seen from the above embodiments, the present disclosure provides a mild, environmentally friendly and efficient preparation method of methyl 2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetate.

[0025] It should be understood that the above general description and the following detailed description are only exemplary and explanatory, and cannot limit the present disclosure. Detailed Description

[0026] To make the objectives, technical solutions and advantages of the present application clearer, the technical solutions of the present application will be clearly and completely described below in conjunction with the embodiments. Apparently, the described embodiments are some, but not all, of the embodiments of the present application. The embodiments described herein are illustrative in nature and are used to provide a basic understanding of the present application. The embodiments of the present application should not be construed as limiting the present application.

[0027] For the sake of brevity, only some numerical ranges are specifically disclosed herein. However, any lower limit can be combined with any upper limit to form a range not explicitly recited; and any lower limit can be combined with other lower limits to form a range not explicitly recited, and similarly any upper limit can be combined with any other upper limit to form a range not explicitly recited. In addition, each individually disclosed point or single numerical value itself can be used as a lower limit or an upper limit and combined with any other point or single numerical value or combined with other lower limits or upper limits to form a range not explicitly recited.

[0028] In this document, the terms "comprising", "including" or any other variation thereof are intended to cover non-exclusive inclusion, such that a process, method, article or apparatus that comprises a series of elements includes not only those elements but also other elements not expressly listed, or elements that are inherent to such process, method, article or apparatus. Without further limitation, an element qualified by the statement "comprising an..." does not exclude the presence of additional identical elements in the process, method, article or apparatus that comprises the element.

[0029] In the description herein, unless otherwise specified, "above" and "below" include the number itself.

[0030] Unless otherwise specified, the terms used in this disclosure have the well-known meanings commonly understood by those skilled in the art. Unless otherwise specified, the numerical values of the various parameters mentioned in this disclosure can be measured by various common measurement methods in the art (for example, they can be tested according to the methods given in the embodiments of this disclosure).

[0031] The term "about" is used to describe and account for small variations. When used in connection with an event or circumstance, the term can refer to instances where the event or circumstance occurs precisely as well as instances where it occurs very nearly. For example, when used in connection with a numerical value, the term can refer to a range of variation of plus or minus 10% of the numerical value, such as plus or minus 5%, plus or minus 4%, plus or minus 3%, plus or minus 2%, plus or minus 1%, plus or minus 0.5%, plus or minus 0.1%, or plus or minus 0.05%. Additionally, sometimes quantities, ratios, and other numerical values are presented in a range format in this document. It should be understood that such range formats are for convenience and brevity and should be interpreted flexibly to include not only the numerical values explicitly specified as range limits but also all individual numerical values or sub-ranges subsumed within the range as if each numerical value and sub-range were explicitly specified.

[0032] A list of items connected by the terms "at least one of", "at least one in", "at least one kind in" or other similar terms can mean any combination of the listed items. For example, if items A and B are listed, then the phrase "at least one of A and B" means only A; only B; or A and B. In another example, if items A, B, and C are listed, then the phrase "at least one of A, B, and C" means only A; or only B; only C; A and B (excluding C); A and C (excluding B); B and C (excluding A); or all of A, B, and C. Item A can include a single component or multiple components. Item B can include a single component or multiple components. Item C can include a single component or multiple components.

[0033] In the present disclosure, the term "alkyl" refers to an aliphatic hydrocarbon group, which may be straight-chain or branched. Branched refers to one or more lower alkyl groups attached to a linear alkyl chain, such as methyl, ethyl or propyl. "Lower alkyl" refers to a group containing from about 1 to about 6 carbon atoms in the chain, which may be straight-chain or branched.

[0034] In the present disclosure, the term "alkenyl" refers to an aliphatic hydrocarbon group which contains at least one carbon-carbon double bond and which may be straight-chain or branched. Branched refers to one or more lower alkyl groups attached to a linear alkenyl chain, such as methyl, ethyl or propyl. "Lower alkenyl" refers to a group containing from about 2 to about 6 carbon atoms in the chain, which may be straight-chain or branched.

[0035] In the present disclosure, the term "aryl" refers to an aromatic monocyclic or polycyclic ring system. The aryl may be optionally substituted with one or more "ring system substituents", which may be the same or different and are as defined herein. Non-limiting examples of suitable aryls include phenyl and naphthyl.

[0036] In the present disclosure, the term "heteroaryl" refers to an aromatic monocyclic or polycyclic ring system in which one or more ring atoms are elements other than carbon, such as nitrogen, oxygen or sulfur, either alone or in combination, and preferably the heteroaryl contains from about 5 to about 6 ring atoms. The "heteroaryl" may be optionally substituted with one or more "ring system substituents", which may be the same or different and are as defined herein. The prefixes aza, oxa or thia before the heteroaryl root name indicate that at least one nitrogen, oxygen or sulfur atom is present as a ring atom, respectively. The nitrogen atom of the heteroaryl may be optionally oxidized to the corresponding N-oxide. Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furyl, phenylthio, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, cinnolinyl, imidazo[1,2-a]pyridyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidinyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzazaindolyl, 1,2,4-triazinyl, benzothiazolyl, etc.

[0037] In the present disclosure, the term "amino" refers to an -NR′R′′ group. The amino group may be optionally substituted. In an unsubstituted amino group, R′ and R′′ are hydrogen. In a substituted amino group, R′ and R′′ may each independently be, but are not limited to, hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, alkylheterocycloalkyl, alkoxy, sulfonyl, alkenyl, alkanoyl, aryl, arylalkyl, or heteroaryl, provided that R′ and R′′ are not both hydrogen. In a substituted amino group, R′ and R′′ may cyclize to form a cyclic amino group, such as pyrrolidinyl or piperidinyl. Such cyclic amino groups may incorporate additional heteroatoms, such as to form piperazine or morpholine groups. Such cyclic amino groups may be optionally substituted, for example, by amino, hydroxy, or oxo groups.

[0038] In the present disclosure, the term "alkoxy" refers to -O-alkyl. An alkoxy group may refer to a straight-chain, branched-chain, or cyclic, saturated or unsaturated oxy-hydrocarbon chain, including, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, and pentyloxy. An alkoxy group may be optionally substituted by one or more alkoxy substituents ("substituted alkoxy").

[0039] In the present disclosure, the term "cycloalkyl" refers to a non-aromatic mono- or polycyclic ring system, and preferably the cycloalkyl ring contains from about 5 to about 7 ring atoms. The cycloalkyl may be optionally substituted by one or more "ring system substituents", which may be the same or different and are as defined above. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. Non-limiting examples of suitable polycyclic cycloalkyls include 1-decahydronaphthyl, norbornyl, adamantyl, etc. In the present disclosure, the term "cycloalkoxy" refers to a group in which one or more carbons in the mono- or polycyclic ring system of "cycloalkyl" are replaced by oxygen atoms.

[0040] In the present disclosure, the term "heterocyclic group" refers to a non-aromatic saturated monocyclic or polycyclic ring system in which one or more of the ring atoms are elements other than carbon, such as nitrogen, oxygen, or sulfur, either individually or in combination. There are no adjacent oxygen and / or sulfur atoms in the ring system, and preferably the heterocycle contains from about 5 to about 6 ring atoms. The prefixes aza-, oxa-, or thia- before the heterocyclic group root name indicate that at least one nitrogen, oxygen, or sulfur atom, respectively, is present as a ring atom. The heterocyclic group may be optionally substituted by one or more "ring system substituents", which may be the same or different and are as defined herein. The nitrogen or sulfur atoms of the heterocyclic group may be optionally oxidized to the corresponding N-oxides, S-oxides, or S,S-dioxides. Non-limiting examples of suitable monocyclic heterocyclic group rings include piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrobenzothienyl, tetrahydrothiopyranyl, etc.

[0041] In the present disclosure, compound A is prepared through the following steps: Step 1-1: At 0 °C, dissolve the aryl / heteroaryl-substituted ketone in ethanol, then add sodium hydroxide thereto; then add the aryl / heteroaryl-substituted aldehyde, and raise the temperature to room temperature for reaction to obtain the aromatic enone intermediate of Step 1-1; the reaction process is shown by the following formula:

[0042] Step 1-2: At low temperature (-20 °C to -70 °C), add the aromatic enone intermediate obtained in Step 1-1 into a container, carry out nitrogen protection, then add anhydrous tetrahydrofuran; then add tribromomethane into the anhydrous tetrahydrofuran, then add it into the aforementioned solution, and then dropwise add NaHMDS (sodium hexamethyldisilazide), after reacting for 10 - 20 min, quench with water, extract three times with ethyl acetate, combine the organic layers, wash with saturated brine, then dry with anhydrous sodium sulfate, and obtain the aryl tribromo intermediate of Step 1-2 through column chromatography; the reaction process is shown by the following formula:

[0043] Step 1-3: Add metal hydride (here it is CaH 2 ), bis(triphenylphosphine)palladium dichloride (Pd(PPh 3 ) 2 Cl 2 ) into tetrahydrofuran, add the aryl tribromo intermediate obtained in Step 1-2 into tetrahydrofuran, mix the two, react at 30 °C, detect by TLC, after the reaction is completed, filter, quench with water, extract three times with ethyl acetate, combine the organic layers, wash with saturated brine, then dry with anhydrous sodium sulfate, and obtain compound A through column chromatography; the reaction process is shown by the following formula:

[0044] In the present disclosure, by selecting different aryl / heteroaryl-substituted ketone raw materials and aryl / heteroaryl-substituted aldehyde raw materials, compound A with different structural formulas can be obtained, and the specific process is shown in Example 1.

[0045] In the present disclosure, for compound A, under the following conditions, compound A can generate compound B and highly activated Br ions:

[0046] And the highly activated Br ions attack the benzyl group in the presence of N,N-diisopropylethylamine to form a carbocation intermediate, and finally form a brominated product.

[0047] In the present disclosure, when Ar 1 and / or Ar 2When the five-membered heterocycle contains a nitrogen atom, compound B has a catalytic effect on the reaction of methyl (E)-2-methoxyimino-[2-(o-methyl)phenyl]acetate to form methyl 2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetate, which helps to accelerate the reaction.

[0048] The following further illustrates the present disclosure in the form of specific examples. All chemical reagents used in the examples of the present disclosure are obtained through conventional commercial channels unless otherwise specified. Unless otherwise specified, the contents described below are mass contents. Unless otherwise specified, it is understood to be carried out at room temperature.

[0049] Example 1: Example 1 includes the following steps: 1. Preparation of compound 1: At 0 °C, 4-acetylimidazole (40 mmol) was dissolved in ethanol (60 mL), and then 10% sodium hydroxide (20 mL) was added thereto; then 4-imidazolecarboxaldehyde (40 mmol) was added, and the temperature was raised to room temperature for reaction to obtain the aromatic enone intermediate of Example 1; the reaction process is shown in the following formula:

[0050] At low temperature (-40 °C), the aromatic enone intermediate of Example 1 was added to a 100 mL container, nitrogen was introduced for protection, and then 30 mL of anhydrous tetrahydrofuran was added; then tribromomethane (18 mmol) was added to 5 mL of anhydrous tetrahydrofuran, and then added to the aforementioned solution, and then NaHMDS (sodium hexamethyldisilazide, 15 mmol) was added dropwise. After reacting for 15 min, the reaction was quenched with water, extracted three times with ethyl acetate, the organic layers were combined, washed with saturated brine, and then dried over anhydrous sodium sulfate, and the aromatic tribromo intermediate of Example 1 was obtained by column chromatography; the reaction process is shown in the following formula:

[0051] Calcium hydride 2 (2.5 mmol), bis(triphenylphosphine)palladium dichloride (Pd(PPh 3 ) 2 Cl 2 , 0.075 mmol) was added to 2 mL of tetrahydrofuran, the aromatic tribromo intermediate of Example 1 was added to 20 mL of tetrahydrofuran, the two were mixed, reacted at 30 °C, detected by TLC, after the reaction was completed, filtered, quenched with water, extracted three times with ethyl acetate, the organic layers were combined, washed with saturated brine, and then dried over anhydrous sodium sulfate, and compound 1 was obtained by column chromatography; the reaction process is shown in the following formula:

[0052] 2. Preparation of methyl 2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetate: Methyl (E)-2-methoxyimino-[2-(o-methyl)phenyl]acetate (30 mmol) was added to 50 mL of DMA to form a first solution, and the previously prepared Compound 1 (15 mmol) was added to 50 mL to form a second solution; under stirring, the second solution and the first solution were mixed, and then N,N-diisopropylethylamine (1.5 mmol) was added to obtain a mixed solution; while maintaining stirring, an initiator azobisisobutyronitrile (0.8 mmol), a reducing agent CaH 2 (6.5 mmol), and a catalyst Pd(PPh 3 ) 2 Cl 2 (0.015 mmol) were added, and the reaction was carried out at 30 °C. After completion of the reaction detected by TLC, the mixture was filtered, extracted three times with ethyl acetate, the organic layers were combined, washed with saturated brine, and then dried over anhydrous sodium sulfate. Methyl 2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetate was obtained by column chromatography.

[0053] Example 2: Example 2 includes the following steps: 1. Preparation of Compound 2: At 0 °C, 2-acetyl-1-pyrroline (40 mmol) was dissolved in ethanol (60 mL), and then 10% sodium hydroxide (20 mL) was added thereto; then 4-imidazolecarboxaldehyde (40 mmol) was added, and the temperature was raised to room temperature for reaction to obtain the aromatic enone intermediate of Example 2; the reaction process is shown in the following formula:

[0054] At low temperature (-40 °C), the aromatic enone intermediate of Example 2 was added to a 100 mL container, nitrogen was introduced for protection, and then 30 mL of anhydrous tetrahydrofuran was added; then tribromomethane (18 mmol) was added to 5 mL of anhydrous tetrahydrofuran, then added to the aforementioned solution, and then NaHMDS (sodium hexamethyldisilazide, 15 mmol) was added dropwise. After reacting for 15 min, the reaction was quenched with water, extracted three times with ethyl acetate, the organic layers were combined, washed with saturated brine, and then dried over anhydrous sodium sulfate. The aromatic tribromo intermediate of Example 2 was obtained by column chromatography; the reaction process is shown in the following formula:

[0055] CaH 2 (2.5 mmol), bis(triphenylphosphine)palladium dichloride (Pd(PPh 3 ) 2 Cl 2, 0.075 mmol) was added to 2 mL of tetrahydrofuran, and the aryltribromo intermediate of Example 2 was added to 20 mL of tetrahydrofuran. The two were mixed and reacted at 30 °C. After TLC detection, the reaction was completed, filtered, quenched with water, extracted three times with ethyl acetate, the organic layers were combined, washed with saturated brine, and then dried over anhydrous sodium sulfate. Compound 2 was obtained by column chromatography. The reaction process is shown in the following formula:

[0056] 2. Preparation of methyl 2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetate: (E)-methyl 2-methoxyimino-[2-(o-methyl)phenyl]acetate (30 mmol) was added to 50 mL of DMA to form a first solution, and the compound 2 (15 mmol) prepared above was added to 50 mL to form a second solution; under stirring, the second solution and the first solution were mixed, and then N,N-diisopropylethylamine (1.5 mmol) was added to obtain a mixed solution; while maintaining stirring, an initiator azobisisobutyronitrile (0.8 mmol), a reducing agent CaH 2 (6.5 mmol) and a catalyst Pd(PPh 3 ) 2 Cl 2 (0.015 mmol) were added, and the reaction was carried out at 30 °C. After TLC detection, the reaction was completed, filtered, extracted three times with ethyl acetate, the organic layers were combined, washed with saturated brine, and then dried over anhydrous sodium sulfate. Methyl 2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetate was obtained by column chromatography.

[0057] Example 3: Example 3 includes the following steps: 1. Preparation of compound 3: At 0 °C, 4-acetylimidazole (40 mmol) was dissolved in ethanol (60 mL), and then 10% sodium hydroxide (20 mL) was added thereto; then 2-pyrrolecarboxaldehyde (40 mmol) was added, and the temperature was raised to room temperature for reaction to obtain the aromatic enone intermediate of Example 3. The reaction process is shown in the following formula:

[0058] At low temperature (-40 °C), the aromatic enone intermediate of Example 3 was added to a 100 mL container, protected by introducing nitrogen, and then 30 mL of anhydrous tetrahydrofuran was added; then tribromomethane (18 mmol) was added to 5 mL of anhydrous tetrahydrofuran, then added to the aforementioned solution, and then sodium hexamethyldisilazide (NaHMDS, 15 mmol) was added dropwise. After reacting for 15 min, the reaction was quenched with water, extracted three times with ethyl acetate, the organic layers were combined, washed with saturated brine, and then dried over anhydrous sodium sulfate. The aromatic tribromo intermediate of Example 3 was obtained by column chromatography; the reaction process is shown in the following formula:

[0059] Calcium hydride 2 (2.5 mmol), bis(triphenylphosphine)palladium dichloride (Pd(PPh 3 ) 2 Cl 2 , 0.075 mmol) was added to 2 mL of tetrahydrofuran, the aromatic tribromo intermediate of Example 3 was added to 20 mL of tetrahydrofuran, the two were mixed, reacted at 30 °C, detected by TLC. After the reaction was completed, it was filtered, quenched with water, extracted three times with ethyl acetate, the organic layers were combined, washed with saturated brine, and then dried over anhydrous sodium sulfate. Compound 3 was obtained by column chromatography; the reaction process is shown in the following formula:

[0060] 2. Preparation of methyl 2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetate: (E)-methyl 2-methoxyimino-[2-(o-tolyl)]acetate (30 mmol) was added to 50 mL of DMA to form a first solution, and the aforementioned prepared compound 3 (15 mmol) was added to 50 mL to form a second solution; under stirring, the second solution and the first solution were mixed, and then N,N-diisopropylethylamine (1.5 mmol) was added to obtain a mixed solution; while maintaining stirring, an initiator azobisisobutyronitrile (0.8 mmol), a reducing agent calcium hydride 2 (6.5 mmol) and a catalyst Pd(PPh 3 ) 2 Cl 2 (0.015 mmol) were added, reacted at 30 °C, detected by TLC. After the reaction was completed, it was filtered, extracted three times with ethyl acetate, the organic layers were combined, washed with saturated brine, and then dried over anhydrous sodium sulfate. Methyl 2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetate was obtained by column chromatography.

[0061] Example 4: Example 4 includes the following steps: 1. Preparation of Compound 4: At 0 °C, 2-acetyl-1-pyrroline (40 mmol) was dissolved in ethanol (60 mL), and then 10% sodium hydroxide (20 mL) was added thereto; then 2-pyrrolecarboxaldehyde (40 mmol) was added, and the temperature was raised to room temperature for reaction to obtain the aromatic enone intermediate of Example 4; the reaction process is shown in the following formula:

[0062] At low temperature (-40 °C), the aromatic enone intermediate of Example 4 was added to a 100 mL container, nitrogen was introduced for protection, and then 30 mL of anhydrous tetrahydrofuran was added; then tribromomethane (18 mmol) was added to 5 mL of anhydrous tetrahydrofuran, then added to the aforementioned solution, and then NaHMDS (sodium hexamethyldisilazide, 15 mmol) was added dropwise. After reacting for 15 min, the reaction was quenched with water, extracted three times with ethyl acetate, the organic layers were combined, washed with saturated brine, and then dried over anhydrous sodium sulfate. The aromatic tribromo intermediate of Example 4 was obtained by column chromatography; the reaction process is shown in the following formula:

[0063] Add CaH 2 (2.5 mmol), bis(triphenylphosphine)palladium dichloride (Pd(PPh 3 ) 2 Cl 2 , 0.075 mmol) to 2 mL of tetrahydrofuran, add the aromatic tribromo intermediate of Example 3 to 20 mL of tetrahydrofuran, mix the two, react at 30 °C, monitor by TLC. After the reaction is completed, filter, quench with water, extract three times with ethyl acetate, combine the organic layers, wash with saturated brine, and then dry over anhydrous sodium sulfate. Compound 4 was obtained by column chromatography; the reaction process is shown in the following formula:

[0064] 2. Preparation of methyl 2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetate: Add (E)-methyl 2-methoxyimino-[2-(o-tolyl)]acetate (30 mmol) to 50 mL of DMA to form a first solution, and add the aforementioned prepared Compound 3 (15 mmol) to 50 mL to form a second solution; under stirring, mix the second solution and the first solution, and then add N,N-diisopropylethylamine (1.5 mmol) to obtain a mixed solution; while maintaining stirring, add initiator azobisisobutyronitrile (0.8 mmol), reducing agent CaH 2 (6.5 mmol) and catalyst Pd(PPh 3) 2 Cl 2 (0.015 mmol), react at 30 °C, monitored by TLC. After the reaction is completed, filter, extract three times with ethyl acetate, combine the organic layers, wash with saturated brine, then dry with anhydrous sodium sulfate, and obtain methyl 2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetate by column chromatography.

[0065] Comparative Example 1: Comparative Example 1 includes the following steps: 1. Preparation of Compound 1: At 0 °C, dissolve 4-acetylimidazole (40 mmol) in ethanol (60 mL), then add 10% sodium hydroxide (20 mL) thereto; then add 4-imidazolecarboxaldehyde (40 mmol), and warm up to room temperature for reaction to obtain the aromatic enone intermediate of Example 2; the reaction process is shown in the following formula:

[0066] At low temperature (-40 °C), add the aromatic enone intermediate of Example 1 to a 100 mL container, protect with nitrogen, and then add 30 mL of anhydrous tetrahydrofuran; then add tribromomethane (18 mmol) to 5 mL of anhydrous tetrahydrofuran, then add the aforementioned solution, and then dropwise add NaHMDS (sodium hexamethyldisilazide, 15 mmol). Quench with water after reacting for 15 min, extract three times with ethyl acetate, combine the organic layers, wash with saturated brine, then dry with anhydrous sodium sulfate, and obtain the aryl tribromo product by column chromatography; the reaction process is shown in the following formula:

[0067] 2. Preparation of methyl 2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetate: Add (E) methyl 2-methoxyimino-[2-(o-tolyl)]acetate (30 mmol) to 50 mL of DMA to form a first solution, and add the aforementioned prepared aryl tribromo product (15 mmol) to 50 mL to form a second solution; under stirring, mix the second solution and the first solution, then add N,N-diisopropylethylamine (1.5 mmol) to obtain a mixed solution; while maintaining stirring, add initiator azobisisobutyronitrile (0.8 mmol), reducing agent CaH 2 (6.5 mmol) and catalyst Pd(PPh 3 ) 2 Cl 2(0.015 mmol), reacted at 30 °C, monitored by TLC. After the reaction was completed, it was filtered, extracted three times with ethyl acetate, the organic layers were combined, washed with saturated brine, then dried over anhydrous sodium sulfate, and methyl 2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetate was obtained by column chromatography.

[0068] The difference between Comparative Example 1 and Example 1 is that Comparative Example 1 used an aryl tribromo product instead of the aryl dibromo product prepared in Example 1.

[0069] Yield test: Samples were taken at 2 h, 4 h, and 6 h after the start of the reaction for preparing methyl 2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetate to test the yield of the product; the test results are shown in Table 1 below.

[0070] Table 1:

[0071] It can be seen that in the present application, when Ar 1 and / or Ar 2 is a five-membered heterocycle containing a nitrogen atom, compound A generates compound B and highly activated Br ions in the reaction. The highly activated Br ions attack the benzyl group in the presence of N,N-diisopropylethylamine to form a carbocation intermediate, and finally a brominated product is formed. Compound B has the following advantages: (1) Compound B contains an electron-donating group (aza five-membered ring), which can increase the electron cloud density of the whole system, making the aromatic electrophilic substitution reaction easier to proceed, thus accelerating the rate of the bromination reaction and contributing to the acceleration of the reaction; (2) Compound B contains an electron-donating group (aza five-membered ring), which can undergo a proton transfer with the highly activated Br ions, making the highly activated Br ions form bromonium ions, thus accelerating the rate of the bromination reaction. The compound 1 prepared in Example 1 accelerates the reaction rate most significantly; while the aryl tribromo product obtained in Comparative Example 1 accelerates the reaction rate worst.

[0072] Those skilled in the art will readily conceive of other embodiments of the present disclosure after considering the specification and practicing the disclosure herein. The present disclosure is intended to cover any variations, uses, or adaptations of the present disclosure that follow the general principles of the present disclosure and include known common knowledge or conventional technical means in the technical field not disclosed in the present disclosure.

Claims

1. A method for preparing methyl 2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetate, characterized in that: The preparation method comprises the following steps: step 1: adding (E) 2-methoxyimino-[2-(o-methyl)phenyl]acetic acid methyl ester to an organic solvent to form a first solution, and adding compound A to the organic solvent to form a second solution; mixing the second solution and the first solution under stirring, and then adding a base to obtain a mixed solution; wherein the structural formula of the compound A contains at least two fluorine atoms; step 2: keeping the mixed solution obtained in step 1 under stirring, adding an initiator, a reducing agent and a catalyst to react and obtain 2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetic acid methyl ester.

2. The preparation method according to claim 1, characterized in that: The initiator is selected from dibenzoyl peroxide and / or azobisisobutyronitrile.

3. The preparation method according to claim 1, characterized in that: The catalyst is selected from a palladium catalyst; the palladium catalyst is selected from at least one of 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride, bistriphenylphosphinepalladium dichloride, palladium acetate, tetrakis(triphenylphosphine)palladium, palladium carbon or palladium trifluoroacetate.

4. The preparation method according to claim 1, characterized in that: The base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, N,N-diisopropylethylamine or triethylamine.

5. The preparation method according to claim 1, characterized in that: The reducing agent is selected from metal hydrides, and the metal hydride is selected from sodium hydride, potassium hydride, calcium hydride, magnesium hydride or barium hydride.

6. The preparation method according to claim 1, characterized in that: Compound A has the following structural formula: , wherein Ar1 and Ar2 are each independently selected from C3-12 cycloalkyl, C6-C12 aryl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl; wherein the C3-12 cycloalkyl, C6-C12 aryl, 3-12 membered heterocyclyl or 5-12 membered heteroaryl is optionally substituted with one or more C1-C10 alkyl, C2-C10 alkenyl, C1-C10 alkoxy, amino, hydroxyl or nitro.

7. The preparation method according to claim 1, characterized in that: Compound A is selected from compounds A-1 to A-4 having the following structural formulas: , wherein X1 and X8 are each independently selected from C, N, O or S; X2, X3, X4, X5, X6, X7 are each independently selected from C or N; R1 and R2 are each independently selected from hydrogen, C1-C10 alkyl, C2-C10 alkenyl, C1-C10 alkoxy, amino, hydroxyl or nitro.

8. The preparation method according to claim 7, characterized in that: Compound A is selected from compounds 4-1-1 to 4-1-3 having the following structural formulas: , wherein R1 and R2 are each independently selected from hydrogen, C1-C10 alkyl, C2-C10 alkenyl, C1-C10 alkoxy, amino, hydroxyl or nitro.

9. The preparation method according to claim 8, characterized in that: Compound A is selected from the following compounds 1: .

10. The preparation method according to claim 1, characterized in that: The organic solvent is selected from dichloroethane, tetrahydrofuran, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, N,N-diethylformamide, N,N-diethylacetamide, cyclohexanone, isophorone or methyl tert-butyl ether.

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