A preparation method of 3-amino-2-fluorobenzoyl halide

Abstract

The present invention discloses a method for preparing 3-amino-2-fluorobenzoyl halide (Formula V), which includes two routes: Route 1, or Route 2, wherein R, R 1， The definition of R2 is as defined in the specification.

Description

Technical Field

[0001] The present invention relates to the field of chemical synthesis, and in particular to a method for preparing 3-amino-2-fluorobenzoyl halide. Background Art

[0002] Isophthalamide insecticides were also discovered accidentally during the research on diamide insecticides. Their characteristic structures are similar to those of diamide insecticides, but their mechanisms of action are different (thus they are often classified as diamide insecticides). Currently, two varieties, brofenac (codenamed MCI-8007 and MIE-1209FL) and cyproflumizone (codenamed CAC-I-785), have been developed. Brofenac is the first isophthalamide insecticide developed by Mitsui Agrochemicals (Japan) through structural optimization of the flubendiamide lead compound. It can be used for public health and to control pests such as flies, termites, ants, cockroaches, Spodoptera litura, cotton bollworm, fall armyworm, cabbage borer, diamondback moth, and yellow-striped flea beetles on crops such as vegetables, beans, and potatoes. Cyproflumizone is an independently developed product derived from the introduction of a cyclopropylmethyl group into the lead compound, brofenoxamide. It exhibits high insecticidal activity against sensitive and resistant lepidopteran pests in crops such as rice, corn, cotton, soybeans, fruit trees, and vegetables. Isophthalamide insecticides offer both rapid and persistent efficacy, lacking cross-resistance with existing varieties, making them a hot topic in current research and development, with promising market prospects. The chemical structures of brofenoxamide and cyproflumizone are as follows:

[0003]

[0004] 3-Amino-2-fluorobenzoyl halide is an important intermediate for the synthesis of bromobenzene and cyclosulfuronid. In the prior art, 3-amino-2-fluorobenzoyl halide is mainly prepared by reacting acid in thionyl chloride. The specific methods for preparing 3-amino-2-fluorobenzoic acid mainly include: 1) 2-fluoro-3-chloroaniline is substituted and hydrolyzed with sodium cyanide to obtain the target product, refer to WO202170124; this method has expensive raw materials, uses highly toxic sodium cyanide, and has relatively harsh operating conditions, which is not suitable for industrial Chemical production; 2) 2-fluorotoluene is nitrated, oxidized, and reductively dehalogenated to obtain the target product, see WO2009137391; this method has poor nitration selectivity, uses potassium permanganate as the oxidizing reagent, has a high risk factor, causes serious environmental pollution, and is not suitable for large-scale production processes; 3) 2,6-dichlorobenzoic acid is nitrated, fluorinated, and dehalogenated to prepare the target product, see CN111320548A; this method has poor fluorination selectivity and isomeric impurities are difficult to remove, resulting in high costs and is not suitable for industrial production.

[0005] In summary, the existing methods for preparing intermediates have disadvantages such as high cost, harsh production environment, and unsuitability for industrial production. Summary of the Invention

[0006] Aiming at various defects in the prior art for synthesizing 3-amino-2-fluorobenzoyl halide compounds, the present invention provides a method for preparing 3-amino-2-fluorobenzoyl chloride and its derivatives, which solves the problems in the prior art.

[0007] The present invention discloses a method for preparing a compound of formula V, and the synthetic route thereof is as follows:

[0008]

[0009] Wherein, R1 is selected from chlorine, bromine or iodine; R is selected from fluorine and chlorine.

[0010] The present invention also provides a preparation method of formula III-a, and its synthetic route is as follows:

[0011] wherein R1 and R2 are independently selected from chlorine, bromine or iodine.

[0012] The present invention also provides another method for preparing the compound of formula V, the synthetic route of which is as follows:

[0013]

[0014] Wherein, R1 and R2 are independently selected from chlorine, bromine or iodine; R is selected from fluorine and chlorine.

[0015] The present invention also provides a preparation method of formula III-b, and its synthetic route is as follows:

[0016] Wherein, R1 and R2 are independently selected from chlorine, bromine or iodine; R is selected from fluorine and chlorine.

[0017] The present invention also provides the following compounds:

[0018] wherein R1 and R2 are independently selected from chlorine, bromine or iodine.

[0019] Beneficial effects

[0020] The route used in the method provided by the present invention is firstly a new route with low raw material cost, less three wastes and high reaction yield; secondly, the acylation reaction in the reaction process realizes the green industrial use between the acid and the acyl chloride; thirdly, a new intermediate compound is synthesized in the synthesis process of the new route, thereby improving the competitiveness of the product and overcoming the problems of low yield and difficulty in removing isomeric impurities in the fluorination process. DETAILED DESCRIPTION

[0021] The endpoints of the ranges and any values ​​disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoints of each range, the endpoints of each range and individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered to be specifically disclosed herein.

[0022] The following is a detailed description of the specific embodiments of the present invention. It should be understood that the specific embodiments described herein are only used to illustrate and explain the present invention and are not intended to limit the present invention.

[0023] The organic acid in the present invention includes monobasic acid or dibasic acid, and the organic acid is exemplified by Q-COOH, or T-SO3H. When it is a dibasic acid, Q may be the same or different, Q is an optionally substituted alkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group, and T is a substituted alkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group. Preferably, the organic acid is at least one selected from formic acid, acetic acid, propionic acid, oxalic acid, benzoic acid, methanesulfonic acid, and p-toluenesulfonic acid, with oxalic acid being particularly preferred.

[0024] In the present invention, C n -C m The subscripts n and m in each case indicate the number of carbon atoms in the group. For example, C1-C6 indicates a group containing 1 to 6 carbon atoms. The alkyl group appearing in the definition of a substituent may be straight-chain or branched, preferably C1-C6 alkyl, such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, sec-butyl, isobutyl, or tert-butyl.

[0025] In the present invention, halogen refers to fluorine, chlorine, bromine and iodine.

[0026] The aryl group in the present invention refers to a monovalent monocyclic or bicyclic aromatic hydrocarbon group of 6 to 10 ring atoms, such as phenyl or naphthyl, but is not limited thereto.

[0027] As used herein, heteroaryl refers to a 5- to 10-membered aromatic monocyclic ring or fused aromatic ring, wherein the aromatic monocyclic ring contains one or more (e.g., 1 to 4, or in certain embodiments, 1 to 3) heteroatoms selected from N, O, and S, with the remaining atoms being carbon; or an aromatic fused ring containing one or more (e.g., 1 to 4, or in certain embodiments, 1 to 3) heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon, wherein at least one heteroatom is present in the aromatic ring. For example, heteroaryl includes a 5- to 10-membered heterocycloalkyl aromatic ring fused to a 5- to 10-membered cycloalkyl or heterocycloalkyl ring. For such fused, bicyclic heteroaryl ring systems in which only one ring contains one or more heteroatoms, the point of attachment may be on either ring. When the total number of S and O atoms in the heteroaryl group exceeds 1, the heteroatoms are not adjacent to each other. In certain embodiments, the total number of S and O atoms in the heteroaryl group does not exceed 2. In certain embodiments, the total number of S and O atoms in the heterocyclic aromatic ring does not exceed 1. Examples of heteroaryl groups include, but are not limited to (numbering from the attachment position as 1), 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,3-pyridazinyl, 3,4-pyridazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,3-pyrazolinyl, 2,4-imidazolinyl, isoxazolinyl, oxazolinyl, thiazolinyl, thiadiazolinyl, tetrazolyl, thienyl, benzothiophenyl, furanyl, benzofuranyl, benzimidazolinyl, indolyl, pyrazinyl, triazolyl, quinolinyl, pyrazolyl, and 5,6,7,8-tetrahydroisoquinolinyl. A divalent radical derived from a monovalent heteroaryl radical whose name ends in "radical" is designated by adding "sub" to the name of the corresponding monovalent radical, e.g., a pyridyl radical having two points of attachment is pyridylene. Heteroaryl does not encompass or overlap with aryl, cycloalkyl, or heterocycloalkyl, which are defined herein.

[0028] In the present invention, optionally substituted means that it may be substituted or unsubstituted. When substituted, the substituent may be alkyl, halogen, hydroxyl, nitro, cyano, etc., but is not limited thereto.

[0029] The present invention first provides a method for preparing a compound of formula V, and the synthetic route thereof is as follows:

[0030]

[0031] Wherein, R1 is selected from chlorine, bromine or iodine; R is selected from fluorine and chlorine.

[0032] In the above preparation method, Formula III-a reacts with a reducing and dehalogenating agent to produce a compound of Formula IV-a. The reducing and dehalogenating agent is hydrogen. The reaction temperature of Formula III-a under the reducing and dehalogenating agent is 30-100°C, preferably 40-60°C, and the hydrogen pressure is 1-3 MPa, preferably 1.5-1.8 MPa. A catalyst is preferably added during the reaction of Formula III-a under the reducing and dehalogenating agent. The catalyst is preferably palladium on carbon or Raney nickel, more preferably palladium on carbon. During the reaction of Formula III-a under the reducing and dehalogenating agent to produce the compound of Formula IV-a, an acid-binding agent is preferably added. The acid-binding agent is selected from an organic base or an inorganic base. The organic or inorganic base is at least one of triethylamine, pyridine, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen hydrate, sodium acetate, sodium methoxide, and sodium ethoxide; triethylamine and / or potassium carbonate are preferred. The molar ratio of compound III-a, catalyst, and acidifying agent is 1:0.02-0.05:1.0-1.5. Preferably, the reaction is carried out in an organic solvent, preferably an alcohol or ether solvent, preferably methanol and ethanol, and preferably tetrahydrofuran and dioxane.

[0033] Preferably, the compound of formula IV-a undergoes an acylation reaction with an organic acid under the catalysis of a Lewis acid; the Lewis acid is ferric chloride, zinc chloride, or aluminum chloride, preferably ferric chloride; the reaction temperature is -20-100°C, preferably 5-25°C; the organic acid is preferably at least one of formic acid, acetic acid, propionic acid, oxalic acid, benzoic acid, methanesulfonic acid, and p-toluenesulfonic acid, particularly preferably oxalic acid; and the molar ratio of the compound of formula IV-a to the organic acid is 1:1.0-2.5. Preferably, the acylation reaction of the compound of formula IV-a with the organic acid under the catalysis of a Lewis acid is carried out in an organic solvent or in the absence of a solvent, and the organic solvent is a halogenated alkane or a benzene solvent, preferably dichloromethane, dichloroethane, and chloroform.

[0034] In the above preparation method, the synthesis of formula III-a can adopt the following synthetic route:

[0035] wherein R1 and R2 are independently selected from chlorine, bromine or iodine.

[0036] In the above preparation method, the compound of formula I is nitrated with a nitrating agent to produce the compound of formula II. The nitration reaction temperature is -20-30°C, preferably -5-5°C; the nitration time is 2-6 hours, preferably 3-4 hours; the nitrating agent is nitric acid, preferably concentrated nitric acid at a concentration of 65-68wt%, and the molar ratio of compound I to nitric acid is 1:1-1.5, preferably 1:1.1-1.2. Preferably, the nitration reaction is carried out in an organic solvent, preferably a halogenated alkane, more preferably one of dichloromethane, dichloroethane and chloroform.

[0037] In the above preparation method, the compound of formula II is fluorinated to produce compound III-a. The fluorination reaction is carried out in a solvent at a temperature of 60°C to 260°C, preferably 80°C to 140°C, and for a time of 6-12 hours, preferably 8-10 hours. The fluorinating agent is selected from potassium fluoride, and the molar ratio of compound II to the fluorinating agent is 1:(1-2.5). The solvent is preferably one or a combination of two of DMF, DMAC, NMP, toluene, xylene, and cyclohexane.

[0038] The present invention also provides a method for preparing a compound of formula V, and the synthetic route thereof is as follows:

[0039]

[0040] Wherein, R1 and R2 are independently selected from chlorine, bromine or iodine; R is selected from fluorine and chlorine.

[0041] In the above preparation method, the compound of formula III-b is fluorinated with a fluorinating agent to produce compound IV-b. The fluorination reaction is carried out in a solvent at a temperature of 60°C to 260°C, preferably 80°C to 140°C, and for a reaction time of 6-12 hours, preferably 8-10 hours. The fluorinating agent is selected from potassium fluoride, and the molar ratio of compound II to the fluorinating agent is 1:(1-2.5). The solvent is preferably one or a combination of two of DMF, DMAC, NMP, toluene, xylene, and cyclohexane.

[0042] In the above preparation method, Formula IV-b reacts with a reducing and dehalogenating agent to produce the compound of Formula V. The reducing and dehalogenating agent is hydrogen. The reaction temperature for Formula IV-b under the reducing and dehalogenating agent is 30-100°C, preferably 40-60°C, and the hydrogen pressure is 1-3 MPa, preferably 1.5-1.8 MPa. Preferably, a catalyst is added during the reaction of Formula IV-b under the reducing and dehalogenating agent. The catalyst is selected from palladium on carbon or Raney nickel, more preferably palladium on carbon. Preferably, an acid-binding agent is added during the reaction of Formula IV-b under the reducing and dehalogenating agent to produce the compound of Formula V. The acid-binding agent is selected from an organic base or an inorganic base. The organic base is at least one of triethylamine, pyridine, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen hydrate, sodium methoxide, sodium acetate, and sodium ethoxide; triethylamine and / or potassium carbonate are preferred. The molar ratio of compound III-a, catalyst, and acidifying agent is 1:0.02-0.05:1.0-1.5. Preferably, the reaction is carried out in an organic solvent, preferably an alcohol or ether solvent, preferably methanol and ethanol, and preferably tetrahydrofuran and dioxane.

[0043] The synthesis method of formula III-b in the above preparation method of the present invention can adopt the following synthetic route:

[0044] Wherein, R1 and R2 are independently selected from chlorine, bromine or iodine; R is selected from fluorine and chlorine.

[0045] In the above synthetic route, the compound of formula I undergoes a nitration reaction with a nitrating agent to produce the compound of formula II. The nitration reaction temperature is -20-30°C, preferably -5-5°C; the nitration time is 2-6 hours, preferably 3-4 hours; the nitrating agent is nitric acid, preferably concentrated nitric acid at a concentration of 65-68wt%, and the molar ratio of compound I to nitric acid is 1:1-1.5, preferably 1:1.1-1.2. Preferably, the nitration reaction is carried out in an organic solvent, preferably a halogenated alkane, more preferably one of dichloromethane, dichloroethane, and chloroform.

[0046] Preferably, in the above synthetic route, the compound of formula II undergoes an acylation reaction with an organic acid under the catalysis of a Lewis acid; the Lewis acid is ferric chloride, zinc chloride, or aluminum chloride, preferably ferric chloride; the reaction temperature is -20-100°C, preferably 5-25°C; the organic acid is an organic acid, preferably at least one of formic acid, acetic acid, propionic acid, oxalic acid, benzoic acid, methanesulfonic acid, and p-toluenesulfonic acid, particularly preferably oxalic acid; the molar ratio of the compound of formula II to the organic acid is 1:1.0-2.5. Preferably, the acylation reaction is carried out in an organic solvent or in the absence of a solvent, and the organic solvent is a halogenated alkane or a benzene solvent, preferably dichloromethane or dichloroethane.

[0047] The present invention discloses the following compounds,

[0048] wherein R1 and R2 are independently selected from chlorine, bromine or iodine. The above-mentioned compound is used to prepare the product of the present invention in a more optimal route with better effects, and can overcome the problem of poor selectivity of the fluorination reaction in the prior art.

[0049] The present invention will be described in detail below by way of examples. In the following examples:

[0050] The amounts of reactants and products were determined by liquid chromatography (Agilent HPLC 1260).

[0051] The conversion and selectivity of the reaction were calculated using the following formula:

[0052] Conversion rate = (molar amount of raw material input - molar amount of raw material remaining in the product) / molar amount of raw material input × 100%.

[0053] Selectivity = actual molar amount of target product / theoretical molar amount of target product × 100%

[0054] Yield = actual mass of target product / theoretical mass of target product × 100%

[0055] Unless otherwise specified, all raw materials used were commercially available products.

[0056] Example 1

[0057] In a four-necked flask equipped with a mechanical stirrer, a thermometer, and a condenser, 26 g of dichloroethane and 26.4 g of 2,5-dichlorotrichlorotoluene (0.1 mol, 99%, purchased from Aladdin) were added, the temperature was kept at 0°C, 11.6 g of 65% nitric acid was added dropwise for nitration, and the reaction was stirred for 3 h. After HPLC detection, the raw materials were complete, dichloroethane and water were added for extraction, and then alkali solution was added to adjust the pH to neutral. The liquid was separated and the water was separated for desolventization to obtain 29.6 g of the compound 3-nitro-2,5-dichloro-trichlorotoluene, with a yield of 96%;

[0058] The NMR data are as follows: 1 H NMR(500MHz,DMSO-d6)δ8.01(1H,s,ArH),7.98(1H,s,ArH);

[0059] The 3-nitro-2,5-dichloro-trichlorotoluene obtained in the previous step was added to a four-necked flask, and 81 g of DMF, 10 g of xylene, and 8.4 g of potassium fluoride were added. The mixture was kept at 90°C for 9 h. After the reaction of the raw materials was completed, the mixture was cooled to room temperature, the salt was filtered out, and the solvent was removed to obtain the compound 3-nitro-2-fluoro-5-chloro-trichlorotoluene with a yield of 90%.

[0060] The NMR data are as follows: 1 H NMR(500MHz,DMSO-d6)δ8.22(1H,s,ArH),7.80(1H,s,ArH);

[0061] Then, the crude product 3-nitro-2-fluoro-5-chloro-trichlorotoluene was added to an autoclave, and 76 g of methanol, 0.5 g of palladium carbon, and 17.8 g of potassium carbonate were added. The autoclave was kept at 50°C and filled with hydrogen at 1.5 MPa. The reaction was carried out for 5 h. After HPLC detection, the raw material was completely completed. The solvent was removed by filtration to obtain 18.6 g of the compound 3-amino-2-fluorotrichlorotoluene, with a yield of 94.5%.

[0062] The NMR data are as follows: 1 H NMR(500MHz,DMSO-d6)δ7.89(2H,m,ArH),7.67(1H,dd,J=7.9Hz,1.4Hz,ArH),5.27(2H,s,N H 2);

[0063] Then add all the 3-amino-2-fluorobenzotrichloride obtained in the previous step into a four-necked flask, add 60g of dichloroethane and 1g of ferric chloride, keep the temperature at 5°C, add 11.0g of oxalic acid in batches, and react for 2h. After the reaction of the raw materials is complete, desolventize and recover the by-product oxalyl chloride to obtain 12.7g of the compound 3-amino-2-fluorobenzoyl chloride, with a yield of 90%;

[0064] Example 2

[0065] The difference from Example 1 is that the compound 2-chloro-5-bromo-trichlorotoluene is used to replace 2,5-dichloro-trichlorotoluene, and the other molar ratios remain unchanged. The reaction produces 13.2 g of 3-amino-2-fluorobenzoyl chloride with a total yield of 76%.

[0066] Example 3

[0067] The synthesized compound 3-nitro-2,5-dichlorobenzotrichloride (0.96 mol) was added to a four-necked flask, and 60 g of dichloroethane and 1 g of ferric chloride were added. The mixture was kept at 5°C, and 9.5 g of oxalic acid was added in batches. The reaction was continued for 2 h. After the reaction of the raw materials was completed, the by-product oxalyl chloride was recovered by desolventizing to obtain 22.5 g of the compound 3-nitro-2,5-dichlorobenzoyl chloride with a yield of 92%.

[0068] Then, 60 g of xylene and 10.8 g of potassium fluoride were added, and the mixture was separated and kept at 140° C. for 9 h. After the reaction of the raw materials was completed, the mixture was cooled to room temperature and the salt was filtered out. After removing the solvent, the mixture was transferred to an autoclave, and 65 g of methanol, 0.6 g of palladium carbon, and 13.1 g of potassium carbonate were added to the autoclave. The mixture was kept at 60° C. and filled with hydrogen at 1.8 MPa. The reaction was continued for 8 h. After HPLC detection, the raw materials were complete, and the mixture was filtered and desolvated to obtain 11.5 g of compound 3-amino-2-fluorobenzoyl fluoride, with a two-step yield of 83%.

[0069] Example 4

[0070] The difference from Example 3 is that acetic acid replaces oxalic acid, and the other molar ratios remain unchanged. The reaction produces 18.3 g of 3-nitro-2,5-dichlorobenzoyl chloride with a yield of 75%.

[0071] Example 5

[0072] The difference from Example 3 is that oxalic acid is replaced by benzoic acid, and the other molar ratios remain unchanged. The reaction produces 21.7 g of 3-nitro-2,5-dichlorobenzoyl chloride with a yield of 89%.

[0073] Example 6

[0074] The difference from Example 3 is that aluminum chloride replaces ferric chloride, and the other molar ratios remain unchanged. The reaction produces 15.1 g of 3-nitro-2,5-dichlorobenzoyl chloride with a yield of 62%.

[0075] The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, various simple variations of the technical solution of the present invention may be made, including combining the various technical features in any other appropriate manner. These simple variations and combinations should also be regarded as disclosed in the present invention and fall within the scope of protection of the present invention.

Claims

1. A method for preparing 3-amino-2-fluorobenzoyl halide represented by formula V, characterized in that: Its synthetic route is as follows: Wherein, R1 is selected from chlorine, bromine or iodine; R is selected from chlorine.

2. The preparation method according to claim 1, characterized in that Formula III-a reacts under the action of a reducing and dehalogenating agent to generate a compound of formula IV-a.

3. The preparation method according to claim 2, characterized in that The reducing and dehalogenating agent is hydrogen.

4. The preparation method according to claim 3, characterized in that During the reaction of formula III-a to generate formula IV-a compound under the action of reduction and dehalogenation agent, a catalyst and an acid binding agent are added, wherein the catalyst is selected from palladium carbon or Raney nickel; and the acid binding agent is an organic base or an inorganic base.

5. The preparation method according to claim 1, characterized in that The compound of formula IV-a undergoes acylation reaction with an organic acid under the catalysis of a Lewis acid to prepare a compound of formula V.

6. The preparation method according to claim 1, characterized in that The synthetic route of formula III-a is as follows: wherein R1 and R2 are independently selected from chlorine, bromine or iodine.

7. The preparation method according to claim 6, characterized in that The compound of formula I is subjected to a nitration reaction with a nitrating agent to generate a compound of formula II.

8. The preparation method according to claim 6, characterized in that The compound of formula II is fluorinated with a fluorination agent to generate compound III-a.

9. Compounds, in, R1 and R2 are each independently selected from chlorine, bromine or iodine.

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