A preparation method of methyl 2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetate

Abstract

The present disclosure relates to the technical field of fine chemicals, and in particular to a method for preparing methyl 2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetate. The method comprises the following steps: stirring and mixing methyl (E)-2-methoxyimino-[2-(o-methyl)phenyl]acetate and compound A, and then adding a base to obtain a mixed solution; wherein compound A is an aryl compound or heteroaryl compound containing at least two fluorine atoms in the structural formula; and then adding an initiator, a reducing agent, and a catalyst to react to obtain methyl 2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetate.

Description

Technical Field

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

[0002] Strobilurins, a new class of fungicides, have been successfully developed using natural products called strobilurins as active lead compounds. These fungicides exhibit broad spectrum properties, good rainwater resistance, and long-lasting efficacy. Methyl 2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetate is a key raw material for the synthesis of strobilurin fungicides such as trifloxystrobin and kresoxim-methyl. Currently, several methods exist for synthesizing methyl 2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetate, but all require large amounts of environmentally damaging raw materials such as acids, bases, and hydrogen peroxide, and the reaction conditions often require high temperatures. Therefore, a milder, environmentally friendly, and efficient method for preparing methyl 2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetate is urgently needed. Summary of the Invention

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

[0004] According to a first aspect of an embodiment of the present disclosure, a method for preparing methyl 2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetate is provided, the preparation method comprising the following steps: Step 1: adding (E) 2-methoxyimino-[2-(o-methyl)phenyl]acetate 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.

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

[0006] In one aspect of the present disclosure, the initiator is selected from dibenzoyl 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 (E) 2-methoxyimino-[2-(o-methyl)phenyl]acetic acid methyl ester, the mass percentage of the initiator is 0.1%-1.2%; preferably, based on the total mass of (E) 2-methoxyimino-[2-(o-methyl)phenyl]acetic acid methyl ester, the mass percentage of the initiator is 0.1%-0.5%; specifically, the mass percentage of the initiator is 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45% or 0.5%; but is not limited thereto.

[0008] In one aspect of the present disclosure, the catalyst is selected from a palladium catalyst; the palladium catalyst is selected from at least one of 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride, bistriphenylphosphine palladium dichloride, palladium acetate, tetrakis(triphenylphosphine)palladium, palladium carbon or palladium trifluoroacetate; preferably, the palladium catalyst is selected from bistriphenylphosphine palladium dichloride.

[0009] In one aspect of the present disclosure, based on the total mass of compound A, the mass percentage of the palladium catalyst is 0.25%-0.75%; specifically, the mass percentage 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 is 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 (E) 2-methoxyimino-[2-(o-methyl)phenyl]acetic acid methyl ester, the mass percentage of the N,N-diisopropylethylamine is 0.8%-2.5%; preferably, based on the total mass of (E) 2-methoxyimino-[2-(o-methyl)phenyl]acetic acid methyl ester, the mass percentage of the N,N-diisopropylethylamine is 1.5%-2.0%; specifically, the mass percentage of the 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 is not limited thereto.

[0012] In one aspect of the present disclosure, 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; 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 is not limited thereto.

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

[0015] wherein Ar1 and Ar2 are each independently selected from a C3-12 cycloalkyl group, a C6-C12 aryl group, a 3-12 membered heterocyclyl group or a 5-12 membered heteroaryl group; wherein the C3-12 cycloalkyl group, the C6-C12 aryl group, the 3-12 membered heterocyclyl group or the 5-12 membered heteroaryl group is optionally substituted with one or more C1-C10 alkyl groups, C2-C10 alkenyl groups, C1-C10 alkoxy groups, amino groups, hydroxyl groups or nitro groups.

[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, 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.

[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 formula:

[0019] wherein R1 and R2 are each independently selected from hydrogen, C1-C10 alkyl, C2-C10 alkenyl, C1-C10 alkoxy, amino, hydroxyl 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 a second aspect of the embodiments of the present disclosure, provided is methyl 2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetate prepared by the aforementioned preparation method.

[0023] According to a third aspect of the embodiments of the present disclosure, there is provided a use of the aforementioned prepared methyl 2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetate in further preparing a methoxyacrylate fungicide.

[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 method for preparing methyl 2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetate.

[0025] It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the disclosure. DETAILED DESCRIPTION

[0026] To make the purpose, technical solutions, and advantages of this application more clear, the technical solutions of this application will be clearly and completely described below in conjunction with the embodiments. Obviously, the described embodiments are part of the embodiments of this application, rather than all the embodiments. The relevant embodiments described herein are illustrative and are used to provide a basic understanding of this application. The embodiments of this application should not be interpreted as limiting this application.

[0027] For the sake of clarity, only some numerical ranges are specifically disclosed herein. However, any lower limit may be combined with any upper limit to form an unspecified range; and any lower limit may be combined with other lower limits to form an unspecified range, and similarly, any upper limit may be combined with any other upper limit to form an unspecified range. In addition, each individually disclosed point or single value may itself serve as a lower limit or upper limit and be combined with any other point or single value, or with other lower limits or upper limits, to form an unspecified range.

[0028] As used herein, the terms "comprises," "comprising," or any other variations thereof are intended to encompass non-exclusive inclusion, such that a process, method, article, or apparatus that includes a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such process, method, article, or apparatus. In the absence of further limitations, an element defined by the phrase "comprising a ..." does not preclude the presence of additional identical elements in the process, method, article, or apparatus that includes 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 commonly understood 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 using various measurement methods commonly used in the art (for example, they can be tested according to the methods given in the examples of this disclosure).

[0031] The term "about" is used to describe and illustrate small changes. When used in conjunction with an event or situation, the term may refer to an example in which the event or situation occurs precisely and an example in which the event or situation occurs very approximately. For example, when used in conjunction with a numerical value, the term may refer to a variation range of less than or equal to ±10% of the numerical value, such as less than or equal to ±5%, less than or equal to ±4%, less than or equal to ±3%, less than or equal to ±2%, less than or equal to ±1%, less than or equal to ±0.5%, less than or equal to ±0.1%, or less than or equal to ±0.05%. In addition, amounts, ratios, and other numerical values are sometimes presented in this article in a range format. It should be understood that such range formats are for convenience and brevity, and should be flexibly understood to include not only numerical values explicitly designated as range limits, but also all individual numerical values or subranges encompassed within the range, as if each numerical value and subrange were explicitly designated.

[0032] A list of items connected by the terms "at least one of," "at least one of," "at least one of," or other similar terms can mean any combination of the listed items. For example, if items A and B are listed, 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, 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 contain a single component or multiple components. Item B can contain a single component or multiple components. Item C can contain a single component or multiple components.

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

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

[0035] In this disclosure, the term "aryl" refers to an aromatic monocyclic or polycyclic ring system. An aryl group 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 aryl groups include phenyl and naphthyl.

[0036] In this disclosure, the term "heteroaryl" refers to an aromatic monocyclic or polycyclic ring system in which one or more of the ring atoms is an element other than carbon, such as nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms. The "heteroaryl" may be optionally substituted by one or more "ring system substituents," which may be the same or different, and are as defined herein. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom, respectively, is present as a ring atom. A nitrogen atom of a heteroaryl may be optionally oxidized to the corresponding N-oxide. Non-limiting examples of suitable heteroaryl groups include pyridinyl, pyrazinyl, furanyl, thiophenyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, 2,3-naphthyridinyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothiophenyl, quinolinyl, imidazolyl, thienopyridinyl, quinazolinyl, thienopyrimidinyl, pyrrolopyridinyl, imidazopyridinyl, isoquinolinyl, benzazaindolyl, 1,2,4-triazinyl, benzothiazolyl, and the like.

[0037] In the present disclosure, the term "amino" refers to a -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" are each independently, but 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 be cyclized to form a cyclic amino group, such as a pyrrolidinyl or piperidinyl group. Such cyclic amino groups may incorporate other heteroatoms, for example, to form a piperazine or morpholine group. Such cyclic amino groups may be optionally substituted, for example, by an amino group, a hydroxyl group, or an oxo group.

[0038] In this disclosure, the term "alkoxy" refers to an -O-alkyl group. Alkoxy can refer to a linear, branched, or cyclic, saturated or unsaturated oxy-hydrocarbon chain, including, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, and pentoxy. Alkoxy can optionally be substituted with 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, preferably a cycloalkyl ring containing about 5 to about 7 ring atoms. The cycloalkyl group may optionally be substituted with one or more "ring system substituents," which may be the same or different and are as defined above. Non-limiting examples of suitable monocyclic cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Non-limiting examples of suitable polycyclic cycloalkyl groups include 1-decalinyl, norbornyl, adamantyl, and the like. In the present disclosure, the term "cycloalkoxy" refers to a group in which one or more carbon atoms of the mono- or polycyclic ring system of a "cycloalkyl" group are replaced by oxygen atoms.

[0040] In this disclosure, the term "heterocyclyl" refers to a non-aromatic saturated monocyclic or polycyclic ring system in which one or more of the ring atoms is an element other than carbon, such as nitrogen, oxygen, or sulfur, either alone or in combination. There are no adjacent oxygen and / or sulfur atoms in the ring system. Preferred heterocycles contain about 5 to about 6 ring atoms. The prefix aza, oxa, or thia before the heterocyclyl root name means that at least a nitrogen, oxygen, or sulfur atom, respectively, is present as a ring atom. The heterocyclyl group may be optionally substituted by one or more "ring system substituents," which may be the same or different, and are defined herein. The nitrogen or sulfur atom of the heterocyclyl group may be optionally oxidized to the corresponding N-oxide, S-oxide, or S,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrophenylthio, tetrahydrothiopyranyl, and the like.

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

[0042]

[0043] Step 1-2: At low temperature (-20°C to -70°C), the aromatic ketene intermediate obtained in step 1-1 is added to a container, protected by nitrogen, and then anhydrous tetrahydrofuran is added; tribromoform is then added to anhydrous tetrahydrofuran, and then added to the above solution, and then NaHMDS (sodium hexamethyldisilazide) is added dropwise. After reacting for 10-20 minutes, water is added to quench the reaction, and the mixture is extracted three times with ethyl acetate. The organic layers are combined, washed with saturated brine, and then dried over anhydrous sodium sulfate. The aromatic tribromo intermediate of step 1-2 is obtained by column chromatography; the reaction process is shown in the following formula:

[0044]

[0045] Step 1-3: Add a metal hydride (here, CaH2) and bistriphenylphosphine palladium dichloride (Pd(PPh3)2Cl2) to tetrahydrofuran, add the aromatic tribromo intermediate obtained in step 1-2 to tetrahydrofuran, mix the two, react at 30°C, and detect by TLC. After the reaction is completed, filter, quench with water, and extract three times with ethyl acetate. Combine the organic layers, wash with saturated brine, and then dry with anhydrous sodium sulfate. Obtain compound A by column chromatography. The reaction process is shown in the following formula:

[0046] 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.

[0047] In the present disclosure, for compound A, compound B and highly activated Br ions can be generated under the following conditions:

[0048]

[0049] The highly activated Br ion attacks the benzyl group in the presence of N,N-diisopropylethylamine to form a carbon cation intermediate and finally a brominated product.

[0050] In the present disclosure, when Ar1 and / or Ar2 is a five-membered heterocycle containing a nitrogen atom, compound B has a catalytic effect on the reaction of (E) 2-methoxyimino-[2-(o-methyl)phenyl]acetic acid methyl ester to form 2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetic acid methyl ester, which helps to accelerate the reaction.

[0051] The present disclosure is further illustrated below by way of specific examples. The various chemical reagents used in the examples of this disclosure were obtained through conventional commercial sources unless otherwise specified. Unless otherwise specified, the amounts described below are by weight. Unless otherwise specified, the results are understood to be at room temperature.

[0052] Example 1: Example 1 includes the following steps: 1. Preparation of Compound 1: 4-acetylimidazole (40 mmol) was dissolved in ethanol (60 mL) at 0°C, 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 ketene intermediate of Example 1; the reaction process is shown in the following formula:

[0053]

[0054] At low temperature (-40°C), the aromatic ketene intermediate of Example 1 was added to a 100 mL container, nitrogen was introduced, and then 30 mL of anhydrous tetrahydrofuran was added; then tribromoform (18 mmol) was added to 5 mL of anhydrous tetrahydrofuran, and then added to the above solution, and then NaHMDS (sodium hexamethyldisilazide, 15 mmol) was added dropwise. After reacting for 15 minutes, water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic layers were combined, washed with saturated brine, and then dried with anhydrous sodium sulfate. The aromatic tribromo intermediate of Example 1 was obtained by column chromatography; the reaction process is shown in the following formula:

[0055]

[0056] CaH2 (2.5 mmol) and bistriphenylphosphine palladium dichloride (Pd(PPh3)2Cl2, 0.075 mmol) were added to 2 mL of tetrahydrofuran, and the aromatic tribromo intermediate of Example 1 was added to 20 mL of tetrahydrofuran. The two were mixed and reacted at 30°C. The reaction was detected by TLC. After the reaction was completed, the mixture was filtered, quenched with water, and extracted three times with ethyl acetate. The organic layers were combined, washed with saturated brine, and then dried with anhydrous sodium sulfate. Compound 1 was obtained by column chromatography. The reaction process is shown in the following formula:

[0057] 2. Preparation of methyl 2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetate: (E)2-methoxyimino-[2-(o-methyl)phenyl]acetate (30 mmol) was added to 50 mL of DMA to form a first solution, and the compound 1 (15 mmol) prepared above was added to 50 mL to form a second solution; the second solution and the first solution were mixed under stirring, 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 CaH2 (6.5 mmol) and a catalyst Pd(PPh3)2Cl2 (0.015 mmol) were added, and the mixture was reacted at 30°C and detected by TLC. After completion of the reaction, the mixture was filtered and extracted three times with ethyl acetate. The organic layers were combined, washed with saturated brine, and then dried over anhydrous sodium sulfate. 2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetate was obtained by column chromatography.

[0058] Example 2: Example 2 includes the following steps: 1. Preparation of Compound 2: 2-acetyl-1-pyrroline (40 mmol) was dissolved in ethanol (60 mL) at 0°C, 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 ketene intermediate of Example 2; the reaction process is shown in the following formula:

[0059]

[0060] At low temperature (-40°C), the aromatic ketene intermediate of Example 2 was added to a 100 mL container, nitrogen was introduced, and then 30 mL of anhydrous tetrahydrofuran was added; then bromoform (18 mmol) was added to 5 mL of anhydrous tetrahydrofuran, and then added to the above solution, and then NaHMDS (sodium hexamethyldisilazide, 15 mmol) was added dropwise. After reacting for 15 minutes, water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic layers were combined, washed with saturated brine, and then dried with anhydrous sodium sulfate. The aromatic tribromo intermediate of Example 2 was obtained by column chromatography; the reaction process is shown in the following formula:

[0061]

[0062] CaH2 (2.5 mmol) and bistriphenylphosphine palladium dichloride (Pd(PPh3)2Cl2, 0.075 mmol) were added to 2 mL of tetrahydrofuran, and the aromatic tribromo intermediate of Example 2 was added to 20 mL of tetrahydrofuran. The two were mixed and reacted at 30°C. The reaction was detected by TLC. After the reaction was completed, the mixture was filtered, quenched with water, and extracted three times with ethyl acetate. The organic layers were combined, washed with saturated brine, and then dried with anhydrous sodium sulfate. Compound 2 was obtained by column chromatography. The reaction process is shown in the following formula:

[0063] 2. Preparation of methyl 2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetate: (E)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; the second solution and the first solution were mixed under stirring, 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 CaH2 (6.5 mmol) and a catalyst Pd(PPh3)2Cl2 (0.015 mmol) were added, and the mixture was reacted at 30°C and detected by TLC. After completion of the reaction, the mixture was filtered and extracted three times with ethyl acetate. The organic layers were combined, washed with saturated brine, and then dried over anhydrous sodium sulfate. 2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetate was obtained by column chromatography.

[0064] Example 3: Example 3 includes the following steps: 1. Preparation of Compound 3: 4-acetylimidazole (40 mmol) was dissolved in ethanol (60 mL) at 0°C, and then 10% sodium hydroxide (20 mL) was added thereto; 2-pyrrolecarboxaldehyde (40 mmol) was then added, and the temperature was raised to room temperature for reaction to obtain the aromatic ketene intermediate of Example 3; the reaction process is shown in the following formula:

[0065]

[0066] At low temperature (-40°C), the aromatic ketene intermediate of Example 3 was added to a 100 mL container, nitrogen was introduced for protection, and then 30 mL of anhydrous tetrahydrofuran was added; then tribromoform (18 mmol) was added to 5 mL of anhydrous tetrahydrofuran, and then added to the above solution, and then NaHMDS (sodium hexamethyldisilazide, 15 mmol) was added dropwise. After reacting for 15 minutes, water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic layers were combined, washed with saturated brine, and then dried with anhydrous sodium sulfate. The aromatic tribromo intermediate of Example 3 was obtained by column chromatography; the reaction process is shown in the following formula:

[0067]

[0068] CaH2 (2.5 mmol) and bistriphenylphosphine palladium dichloride (Pd(PPh3)2Cl2, 0.075 mmol) were added to 2 mL of tetrahydrofuran, and the aromatic tribromo intermediate of Example 3 was added to 20 mL of tetrahydrofuran. The two were mixed and reacted at 30°C. The reaction was detected by TLC. After the reaction was completed, the reaction was filtered, quenched with water, and extracted three times with ethyl acetate. The organic layers were combined, washed with saturated brine, and then dried with anhydrous sodium sulfate. Compound 3 was obtained by column chromatography. The reaction process is shown in the following formula:

[0069] 2. Preparation of methyl 2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetate: (E)2-methoxyimino-[2-(o-methyl)phenyl]acetate (30 mmol) was added to 50 mL of DMA to form a first solution, and the compound 3 (15 mmol) prepared above was added to 50 mL to form a second solution; the second solution and the first solution were mixed under stirring, 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 CaH2 (6.5 mmol) and a catalyst Pd(PPh3)2Cl2 (0.015 mmol) were added, and the mixture was reacted at 30°C and detected by TLC. After completion of the reaction, the mixture was filtered and extracted three times with ethyl acetate. The organic layers were combined, washed with saturated brine, and then dried over anhydrous sodium sulfate. 2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetate was obtained by column chromatography.

[0070] Example 4: Example 4 includes the following steps: 1. Preparation of Compound 4: 2-acetyl-1-pyrroline (40 mmol) was dissolved in ethanol (60 mL) at 0°C, and then 10% sodium hydroxide (20 mL) was added thereto; 2-pyrrolecarboxaldehyde (40 mmol) was then added, and the temperature was raised to room temperature for reaction to obtain the aromatic ketene intermediate of Example 4; the reaction process is shown in the following formula:

[0071]

[0072] At low temperature (-40°C), the aromatic ketene intermediate of Example 4 was added to a 100 mL container, nitrogen was introduced, and then 30 mL of anhydrous tetrahydrofuran was added; then tribromoform (18 mmol) was added to 5 mL of anhydrous tetrahydrofuran, and then added to the above solution, and then NaHMDS (sodium hexamethyldisilazide, 15 mmol) was added dropwise. After reacting for 15 minutes, water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic layers were combined, washed with saturated brine, and then dried with anhydrous sodium sulfate. The aromatic tribromo intermediate of Example 4 was obtained by column chromatography; the reaction process is shown in the following formula:

[0073]

[0074] CaH2 (2.5 mmol) and bistriphenylphosphine palladium dichloride (Pd(PPh3)2Cl2, 0.075 mmol) were added to 2 mL of tetrahydrofuran, and the aromatic tribromo intermediate of Example 3 was added to 20 mL of tetrahydrofuran. The two were mixed and reacted at 30°C. The reaction was detected by TLC. After the reaction was completed, the mixture was filtered, quenched with water, and extracted three times with ethyl acetate. The organic layers were combined, washed with saturated brine, and then dried with anhydrous sodium sulfate. Compound 4 was obtained by column chromatography. The reaction process is shown in the following formula:

[0075] 2. Preparation of methyl 2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetate: (E)2-methoxyimino-[2-(o-methyl)phenyl]acetate (30 mmol) was added to 50 mL of DMA to form a first solution, and the compound 3 (15 mmol) prepared above was added to 50 mL to form a second solution; the second solution and the first solution were mixed under stirring, 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 CaH2 (6.5 mmol) and a catalyst Pd(PPh3)2Cl2 (0.015 mmol) were added, and the mixture was reacted at 30°C and detected by TLC. After completion of the reaction, the mixture was filtered and extracted three times with ethyl acetate. The organic layers were combined, washed with saturated brine, and then dried over anhydrous sodium sulfate. 2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetate was obtained by column chromatography.

[0076] Comparative Example 1: Comparative Example 1 comprises the following steps: 1. Preparation of Compound 1: 4-acetylimidazole (40 mmol) was dissolved in ethanol (60 mL) at 0°C, and then 10% sodium hydroxide (20 mL) was added thereto; 4-imidazolecarboxaldehyde (40 mmol) was then added, and the temperature was raised to room temperature for reaction to obtain the aromatic ketene intermediate of Example 2; the reaction process is shown in the following formula:

[0077]

[0078] At low temperature (-40°C), the aromatic ketene intermediate of Example 1 was added to a 100 mL container, nitrogen was introduced, and then 30 mL of anhydrous tetrahydrofuran was added; then bromoform (18 mmol) was added to 5 mL of anhydrous tetrahydrofuran, and then added to the above solution, and then NaHMDS (sodium hexamethyldisilazide, 15 mmol) was added dropwise. After reacting for 15 minutes, water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate. The organic layers were combined, washed with saturated brine, and then dried with anhydrous sodium sulfate. The aromatic tribromo product was obtained by column chromatography; the reaction process is shown in the following formula:

[0079]

[0080] 2. Preparation of methyl 2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetate: (E)2-methoxyimino-[2-(o-methyl)phenyl]acetate (30 mmol) was added to 50 mL of DMA to form a first solution. The aromatic tribromo product (15 mmol) prepared above was added to 50 mL to form a second solution. The second solution and the first solution were mixed under stirring, and then N,N-diisopropylethylamine (1.5 mmol) was added to obtain a mixed solution. While maintaining stirring, add initiator azobisisobutyronitrile (0.8 mmol), reducing agent CaH2 (6.5 mmol) and catalyst Pd(PPh3)2Cl2 (0.015 mmol), react at 30°C, and detect by TLC. After the reaction is completed, filter, add ethyl acetate and extract three times, combine the organic layers, wash with saturated brine, and then dry with anhydrous sodium sulfate, and obtain 2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetic acid methyl ester by column chromatography.

[0081] The difference between Comparative Example 1 and Example 1 is that Comparative Example 1 uses an aromatic tribromo product instead of the aromatic dibromo product prepared in Example 1.

[0082] Yield test: Samples were taken 2 hours, 4 hours, and 6 hours after the start of the reaction to prepare methyl 2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetate to test the yield of the product; the test results are shown in Table 1 below.

[0083] Table 1:

[0084] It can be seen that in the present application, when Ar1 and / or Ar2 are five-membered heterocycles containing nitrogen atoms, compound A generates compound B and highly activated Br ions during the reaction. The highly activated Br ions attack the benzyl group in the presence of N,N-diisopropylethylamine to form a carbon cation intermediate, and finally form a bromination product. Compound B has the following advantages: (1) Compound B contains an electron-donating group (nitrogen five-membered ring), which can increase the electron cloud density of the entire system, making the aromatic electrophilic substitution reaction easier to proceed, thereby accelerating the rate of the bromination reaction and helping to accelerate the reaction; (2) Compound B contains an electron-donating group (nitrogen five-membered ring), which can undergo proton transfer with the highly activated Br ions, so that the highly activated Br ions form bromide ions, thereby accelerating the rate of the bromination reaction. The compound 1 prepared in Example 1 has the most obvious reaction acceleration rate; while the aromatic tribromo product obtained in Comparative Example 1 has the worst reaction acceleration rate.

[0085] Those skilled in the art will readily appreciate other embodiments of the present disclosure after considering the specification and practicing the disclosure disclosed herein. This 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 common knowledge or customary techniques in the art not disclosed herein.

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: Add (E) 2-methoxyimino-[2-(o-methyl)phenyl]acetate to an organic solvent to form a first solution, and add compound A to the organic solvent to form a second solution; mix the second solution and the first solution under stirring, and then add a base to obtain a mixed solution; wherein the compound A is selected from a compound having the following structural formula: wherein R1 and R2 are each independently selected from hydrogen, C1-C10 alkyl, C2-C10 alkenyl, C1-C10 alkoxy, amino, hydroxyl or nitro; Step 2: While keeping the mixed solution obtained in step 1 in a stirring state, add an initiator, a reducing agent and a catalyst to react to obtain methyl 2-(2-(bromomethyl)phenyl)-2-(methoxyimino)acetate.

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 is selected from the following compound 1: 。 7. 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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