Preparation method of 3-amino-2-fluorobenzoyl chloride and derivatives thereof

Abstract

The invention discloses a preparation method of 3-amino-2-fluorobenzoyl chloride and a derivative thereof (a formula A-V or a formula B-VI), wherein the formula A-V can adopt the following synthetic route: a route I: # imgabs0 # or a route II: # imgabs1 # and the formula B-VI can adopt the following synthetic route: a route a: # imgabs2 # or a route b: # imgabs3 #, and R, R1, R2, R3, R4, R5 and R6 are defined in the specification. Compared with the prior art, the process route of the preparation method has more competitive advantages.

Description

Technical Field

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

[0002] Isophthalamide insecticides were also discovered accidentally during the research of 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, bromofenac (codenamed MCI-8007 and MIE-1209FL) and cyprofenac (codenamed CAC-I-785), have been developed. Among them, bromofenac is the first isophthalamide insecticide obtained by Mitsui Agrochemicals (Mitsui) of Japan through structural optimization of flubendiamide lead compounds. It can be used for public health and the control of pests such as flies, termites, ants, cockroaches, armyworms, cotton bollworms, fall armyworms, cabbage borers, diamondback moths and yellow flea beetles in crops such as vegetables, beans and potatoes. BASF first obtained the product's registration as a sanitary insecticide in Australia in 2019, and subsequently obtained pesticide registrations in China and Japan, while registrations in the United States, Brazil, Canada, Mexico, India and Australia are also in progress. Cyprodinilflumizone is an independently developed variety obtained by introducing cyclopropylmethyl into the lead compound bromofenac. It has high insecticidal activity against sensitive and resistant lepidopteran pests of crops such as rice, corn, cotton, soybeans, fruit trees and vegetables. At present, this variety has become a blockbuster product of strategic cooperation with Syngenta, and pesticide registration in China is also in progress. Isophthalamide insecticides have both good rapid and long-lasting effects, and have no cross-resistance to existing varieties. They have become a hot spot in current research and development and have very broad market prospects. The chemical structures of bromofenac and cyprodinilflumizone are shown in the following formula.

[0003]

[0004] 3-Amino-2-fluorobenzoyl chloride and its derivatives are important intermediates for synthesizing the above pesticide compounds. In the prior art, the above intermediates are usually prepared by acylation reaction of 3-amino-2-fluorobenzoic acid.

[0005] There are three main methods for preparing 3-amino-2-fluorobenzoic acid in the prior art:

[0006] 1) Method A, reference is US200614761 / WO202170124, the synthesis route is:

[0007] Using 2-fluoro-3-chloroaniline as raw material, the target product is obtained by substitution and hydrolysis with sodium cyanide; the starting raw material of this method is relatively expensive, and highly toxic sodium cyanide is used, and the operating conditions are relatively harsh, which is not suitable for industrial production;

[0008] 2) Method B, referenced in WO2009137391, has a synthetic route of: using 2-fluorotoluene as a raw material, nitrification, potassium permanganate oxidation, palladium carbon hydrogenation reduction dehalogenation to obtain the target product; the nitration step of this method has poor selectivity, and the separation of ortho- and para-nitration products is difficult, and potassium permanganate is used as an oxidizing agent, which has a high risk factor and serious environmental pollution, and is not suitable for large-scale production processes;

[0009] 3) Method C, referenced in CN111320548A, has a synthetic route of: using 2,6-dichlorobenzoic acid as a raw material, and preparing the target product through nitration, fluorination and dehalogenation; this method has a high nitration selectivity, but a poor fluorination selectivity (product: isomer = 30:1), and the generated isomer impurities are difficult to remove, resulting in a high production cost, and is not suitable for industrial production.

[0010] In summary, the existing methods for preparing 3-amino-2-fluorobenzoyl chloride and its derivative intermediates have the disadvantages of high cost, poor production environment, and unsuitability for industrial production, resulting in high production costs. Summary of the invention

[0011] Aiming at the defects existing in the prior art in preparing 3-amino-2-fluorobenzoyl chloride and its derivative intermediates, the present invention provides a preparation method of 3-amino-2-fluorobenzoyl chloride and its derivatives.

[0012] Specifically, the present invention discloses a method for synthesizing formula AV, which can adopt the following synthetic route:

[0013] Route I:

[0014]

[0015] or

[0016] Route II:

[0017]

[0018] Wherein, R1, R2 are each independently selected from chlorine, bromine or iodine; R is selected from hydrogen, halogen, hydroxyl, amino, amine, alkoxy, heteroaryl, aryl.

[0019] In the above synthesis method, the compound of formula A-III-a is synthesized by the following route: Wherein, R1 and R2 are as defined above.

[0020] In the above synthesis method, the A-III-b compound is synthesized by the following route:

[0021]

[0022] Wherein, R1 and R2 are as defined above.

[0023] The present invention also provides another method for synthesizing the compound of formula B-VI, which can be synthesized by the following route:

[0024] Route A:

[0025]

[0026] or

[0027] Route B:

[0028]

[0029] Wherein, R3 and R4 are each independently selected from chlorine, bromine or iodine; R5 and R6 are each independently selected from fluorine, chlorine, bromine or iodine and alkoxy.

[0030] In the above synthesis method, the B-III-a compound is synthesized by the following synthesis route:

[0031]

[0032] In the above synthesis method, the B-III-b compound is synthesized by the following synthesis route:

[0033]

[0034] Wherein, R3 and R4 are each independently selected from chlorine, bromine or iodine; R5 and R6 are each independently selected from fluorine, chlorine, bromine or iodine and alkoxy.

[0035] Beneficial Effects

[0036] The synthesis route in the method provided by the present invention is brand new, the raw material cost used is low, the nitration selectivity is high, the fluorination temperature is low, the selectivity is high, no tar is generated, the energy consumption is low, it is suitable for industrialization, and the market competitiveness is improved. DETAILED DESCRIPTION

[0037] The endpoints and any values ​​of the ranges disclosed in this article 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 endpoint values ​​of each range, the endpoint values ​​of each range and the 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 as specifically disclosed in this article.

[0038] The halogen in the present invention refers to fluorine, chlorine, bromine or iodine.

[0039] The term "alkyl" as used herein (and in other groups containing alkyl, e.g. the alkyl moiety of alkoxy, the alkyl moiety of arylalkyl) means in each case a straight-chain or branched alkyl group having usually 1 to 20 carbon atoms, frequently 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, and in particular 1 to 3 carbon atoms. Examples of C1-C6 alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), pentyl and hexyl.

[0040] The amino group in the present invention refers to -NH2

[0041] The amino group in the present invention refers to -NR7R8, wherein R7 and R8 are independently selected from hydrogen and alkyl, preferably H, C1-C6 alkyl.

[0042] The alkoxy group in the present invention is preferably a C1-C6 alkoxy group, exemplified by methoxy, ethoxy, propoxy, and the like, but not limited thereto.

[0043] 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.

[0044] In the present invention, heteroaryl refers to heteroaryl refers to 5 to 10-membered aromatic monocyclic rings, aromatic condensed rings, wherein the aromatic monocyclic ring contains one or more (such as 1 to 4, or in some embodiments 1 to 3) heteroatoms selected from N, O and S and the remaining atoms are carbon; aromatic condensed rings, which contain one or more (such as 1 to 4, or in some embodiments 1 to 3) heteroatoms selected from N, O and S and the remaining ring atoms are carbon, and 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 the fused, bicyclic heteroaromatic ring system in which only one ring contains one or more heteroatoms, the connection point can be on either ring. When the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in the heteroaryl group does not exceed 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle 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, imidazolyl, and 5,6,7,8-tetrahydroisoquinolinyl. Divalent radicals derived from a monovalent heteroaryl radical whose name ends in "yl" by removing a hydrogen atom from the carbon with the free valence are named by adding "sub" to the name of the corresponding monovalent radical, e.g. a pyridyl radical having two points of attachment is a pyridylidene radical.

[0045] The specific embodiments of the present invention are described in detail below. It should be understood that the specific embodiments described herein are only used to illustrate and explain the present invention, and are not used to limit the present invention.

[0046] The present invention first provides a method for synthesizing a compound of formula AV, which can be prepared by the following synthetic route:

[0047] Route I:

[0048]

[0049] Or Route II:

[0050]

[0051] Wherein, R1, R2 are each independently selected from chlorine, bromine or iodine; R is selected from hydrogen, halogen, hydroxyl, amino, amine, alkoxy, heteroaryl, aryl.

[0052] In the above-mentioned route I synthesis method, A-III-a is hydrogenated by hydrogenation to obtain A-IV-a, the hydrogenation reaction temperature is 30-100°C, preferably 40-60°C; the hydrogenation reaction pressure is 1-3MPa, preferably 1.5-1.8MPa, and the hydrogenation catalyst added to the hydrogenation reaction is selected from palladium carbon or Raney nickel, preferably palladium carbon. Preferably, an acid binding agent is added to the hydrogenation reaction, and 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, sodium methoxide, and sodium ethoxide; preferably triethylamine and / or potassium carbonate. Preferably, in the hydrogenation reaction, the molar ratio of A-III-a compound, palladium and acidifying agent is 1:0.02-0.05:1.0-1.5; preferably, the hydrogenation reaction is carried out in a solvent, and the solvent is preferably an alcohol solvent and a benzene solvent, and more preferably methanol and ethanol.

[0053] In the above-mentioned route II synthesis method, A-IV-b is hydrogenated to obtain AV by hydrogenation, the hydrogenation reaction temperature is 30-100°C, preferably 40-60°C; the hydrogenation reaction pressure is 1-3MPa, preferably 1.5-1.8MPa, and the hydrogenation reaction is added with a hydrogenation catalyst selected from palladium carbon or Raney nickel, preferably palladium carbon. Preferably, an acid binding agent is added to the hydrogenation reaction, and 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, sodium methoxide, and sodium ethoxide; preferably triethylamine and / or potassium carbonate. Preferably, in the hydrogenation reaction, the molar ratio of A-IV-b compound, palladium and acidifying agent is 1:0.02-0.05:1.0-1.5; preferably, the hydrogenation reaction is carried out in a solvent, and the solvent is preferably an alcohol solvent and a benzene solvent, and more preferably methanol and ethanol.

[0054] In the above-mentioned route I synthesis method, compound A-IV-a is subjected to cyano hydrolysis reaction to prepare compound A-V, the reaction temperature of the cyano hydrolysis reaction is 0-100°C, preferably 20-60°C; the cyano hydrolysis reaction is carried out under acidic or alkaline conditions by adding a reaction reagent, and the reaction reagent is selected from the corresponding raw materials according to the target product, for example, an alcohol solution of an alcohol or amine or a product prepared as needed is added to the corresponding raw material to generate a corresponding ester, amide, etc. Preferably, the molar ratio of compound A-IV-a to the reaction reagent is 1:1.0-1.5.

[0055] In the above-mentioned route II synthesis method, compound A-III-b is reacted with a fluorinating agent to obtain compound A-IV-b, and the fluorinating reaction is carried out in a solvent or without a solvent, and the reaction temperature is 60°C to 260°C, preferably 80°C to 140°C; the reaction time is 6-10h, preferably 8-9h. The fluorinating agent is selected from potassium fluoride, and the molar ratio of the compound of formula A-II or the compound of formula B-II to the fluorinating agent is 1:(1-1.5). The solvent is preferably one or a combination of two of DMF, DMAC, DMSO, toluene, xylene and cyclohexane.

[0056] In the above synthesis method, the compound of formula A-III-a is synthesized by the following route: Wherein, R1 and R2 are each independently selected from chlorine, bromine or iodine.

[0057] In the above synthesis method, the compound of formula AI is prepared by nitration reaction with a nitrating agent to obtain compound A-II, the nitration reaction temperature is -20-30°C, preferably -5-5°C; the nitration time is 2-6h, preferably 3-4h; the nitration agent is concentrated nitric acid, preferably the concentration of concentrated nitric acid is 65-68wt%, and the molar ratio of compound AI to the nitration agent is 1:1-1.5, preferably 1:1.1-1.2. Preferably, the nitration reaction is carried out in an organic solvent, and the organic solvent is preferably a halogenated alkane, more preferably dichloromethane, dichloroethane or chloroform.

[0058] In the above synthesis method, compound A-II and a fluorinating agent are subjected to a fluorination reaction to prepare compound A-III-a, the fluorination reaction is carried out in a solvent or without a solvent, the reaction temperature is 60°C to 260°C, preferably 80°C to 140°C; the reaction time is 6-10h, preferably 8-9h; the fluorinating agent is selected from potassium fluoride, and the molar ratio of the compound of formula A-II to the fluorinating agent is 1: (1-1.5). The solvent is preferably one or a combination of two of DMF, DMAC, DMSO, toluene, xylene and cyclohexane.

[0059] In the above synthesis method, compound A-III-b is synthesized by the following route: Wherein, R1, R2 are each independently selected from chlorine, bromine or iodine; R is selected from hydrogen, halogen, hydroxyl, amino, amine, alkoxy, heteroaryl, aryl.

[0060] In the above synthesis method, the compound of formula AI is prepared by nitration reaction with a nitrating agent to obtain compound A-II, the nitration reaction temperature is -20-30°C, preferably -5-5°C; the nitration time is 2-6h, preferably 3-4h; the nitration agent is concentrated nitric acid, preferably the concentration of concentrated nitric acid is 65-68wt%, and the molar ratio of compound AI to the nitration agent is 1:1-1.5, preferably 1:1.1-1.2. Preferably, the nitration reaction is carried out in an organic solvent, and the organic solvent is preferably a halogenated alkane, more preferably dichloromethane, dichloroethane or chloroform.

[0061] In the above synthesis method, the cyano group of compound A-II is hydrolyzed to prepare compound A-III-b, the reaction temperature of the cyano group hydrolysis reaction is 0-100°C, preferably 20-60°C; the cyano group hydrolysis reaction is carried out under acidic or alkaline conditions by adding a reaction reagent, and the reaction reagent is selected from the corresponding raw materials according to the target product, for example, an alcohol solution of an alcohol or an amine or a product prepared as needed is added to the corresponding raw material to generate the corresponding ester, amide, etc. Preferably, the molar ratio of compound A-IV-a to the reaction reagent is 1:1.0-1.5.

[0062] The present invention also provides a method for synthesizing a compound of formula B-VI, which can adopt the following synthetic routes: Route a:

[0063]

[0064] or

[0065] Route B:

[0066]

[0067] Wherein, R3 and R4 are each independently selected from chlorine, bromine or iodine; R5 and R6 are each independently selected from fluorine, chlorine, bromine or iodine and alkoxy.

[0068] In the above synthesis method, compound B-III-a is hydrogenated to prepare compound B-IV-a, the hydrogenation reaction temperature is 30-100°C, preferably 40-60°C; the hydrogenation reaction pressure is 1-3MPa, preferably 1.5-1.8MPa, the hydrogenation reaction adds a hydrogenation catalyst selected from palladium carbon or Raney nickel, preferably palladium carbon; preferably, an acid binding agent is added to the hydrogenation reaction, and 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 acetate, sodium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen, sodium methoxide, and sodium ethoxide; preferably triethylamine and / or potassium carbonate. Preferably, in the hydrogenation reaction, the molar ratio of compound B-III-a, palladium and acid binding agent is 1:0.02-0.05:1.0-1.5; preferably, the hydrogenation reaction is carried out in a solvent, and the solvent is preferably an alcohol solvent, an ether solvent, a benzene solvent, and more preferably methanol and dioxane.

[0069] In the above synthesis method, the B-IV-a compound is hydrolyzed to prepare the BV compound, and the reaction temperature of the hydrolysis reaction is 20-150°C, preferably 40-80°C; the hydrolysis reaction is carried out in the presence of an acid, and the acid is an organic acid and an inorganic acid, including formic acid, acetic acid, sulfuric acid, hydrochloric acid, phosphoric acid, preferably formic acid.

[0070] In the above synthesis method, the BV compound and the chlorination reagent are subjected to a chlorination reaction to prepare the B-VI compound, and the chlorination reaction temperature is 0-150°C, preferably 20-60°C; the chlorination reagent is one of thionyl chloride, sulfonyl chloride, NCS, dichlorohydantoin, trichloroisocyanuric acid and chlorine; the molar ratio of compound B-V to the chlorination reagent is 1:1.0-1.5.

[0071] In the above synthesis method, the B-III-b compound reacts with a fluorinating agent to prepare the B-IV-b compound, the fluorinating reaction is carried out in a solvent or without a solvent, the fluorinating reaction temperature is 60°C to 260°C, preferably 80°C to 140°C; the reaction time is 6-10h, preferably 8-9h. The fluorinating agent is selected from potassium fluoride, and the molar ratio of the B-III-b compound to the fluorinating agent is 1: (1-1.5). The solvent is preferably one or a combination of two of DMF, DMAC, DMSO, toluene, xylene and cyclohexane.

[0072] In the above synthesis method, the B-IV-b compound is hydrogenated to prepare the BV compound, the hydrogenation reaction temperature is 30-100°C, preferably 40-60°C; the hydrogenation reaction pressure is 1-3MPa, preferably 1.5-1.8MPa, the hydrogenation reaction adds a hydrogenation catalyst selected from palladium carbon or Raney nickel, preferably palladium carbon, preferably, an acid binding agent is added to the hydrogenation reaction, and 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, sodium acetate, potassium carbonate, sodium hydrogen, sodium methoxide, and sodium ethoxide; preferably triethylamine and / or potassium carbonate. Preferably, in the hydrogenation reaction, the molar ratio of the B-III-a compound, palladium and the acid binding agent is 1:0.02-0.05:1.0-1.5; preferably, the hydrogenation reaction is carried out in a solvent, and the solvent is preferably an alcohol solvent, an ether solvent and a benzene solvent, and more preferably methanol and dioxane.

[0073] In the above synthesis method, the B-III-a compound is synthesized by the following synthesis route:

[0074]

[0075] Wherein R3, R4 are each independently selected from chlorine, bromine or iodine; R5, R6 are each independently selected from fluorine, chlorine, bromine or iodine and alkoxy.

[0076] In the above synthesis method, compound BI and a nitrating agent undergo a nitration reaction to obtain compound B-II, the nitration reaction temperature is -20-30°C, preferably -5-5°C; the nitration time is 2-6h, preferably 3-4h; the nitration agent is concentrated nitric acid, preferably the concentration of concentrated nitric acid is 65-68wt%, and the molar ratio of compound BI to the nitrating agent is 1:1-1.5, preferably 1:1.1-1.2. Preferably, the nitration reaction is carried out in an organic solvent, and the organic solvent is preferably a halogenated alkane, more preferably dichloromethane, dichloroethane or chloroform.

[0077] In the above synthesis method, the B-II compound is subjected to a fluorination reaction with a fluorinating agent to prepare the B-III-a compound. The fluorination reaction is carried out in a solvent or without a solvent. The fluorination reaction temperature is 60°C to 260°C, preferably 80°C to 140°C; the reaction time is 6-10h, preferably 8-9h. The fluorinating agent is selected from potassium fluoride, and the molar ratio of the B-II compound to the fluorinating agent is 1:(1-1.5). The solvent is preferably one or a combination of two of DMF, DMAC, DMSO, toluene, xylene and cyclohexane.

[0078] In the above synthesis method, the B-III-b compound is synthesized by the following synthesis route:

[0079]

[0080] Wherein R3, R4 are each independently selected from chlorine, bromine or iodine; R5, R6 are each independently selected from fluorine, chlorine, bromine or iodine and alkoxy.

[0081] In the above synthesis method, the preparation method of compound B-II is as described above. Compound B-III-b is prepared by hydrolysis of compound B-II, and the hydrolysis reaction is carried out in the presence of an acid, which is an organic acid and an inorganic acid, formic acid, acetic acid, sulfuric acid, hydrochloric acid, phosphoric acid, preferably formic acid; the reaction temperature is 20-150°C, preferably 40-80°C.

[0082] The present invention will be described in detail below by way of examples. In the following examples:

[0083] The amounts of reactants and products were determined by liquid chromatography (Agilent HPLC 1260).

[0084] The conversion and selectivity of the reaction were calculated by the following formula:

[0085] Conversion rate = (molar amount of raw material input - molar amount of raw material remaining in the product) / molar amount of raw material input × 100%.

[0086] Selectivity = actual molar amount of target product / theoretical molar amount of target product × 100%

[0087] Yield = actual mass of target product / theoretical mass of target product × 100%

[0088] Unless otherwise specified, all raw materials used were commercially available products.

[0089] Example 1

[0090] In a four-necked flask equipped with a mechanical stirrer, a thermometer, and a condenser, add 17 g of dichloroethane and 17.2 g of 2,5-dichlorobenzonitrile (0.1 mol, 99%, purchased from Aladdin), keep warm at 0°C, drop 11.6 g of 65% nitric acid for nitration, stir and react for 3 h, HPLC detects that the raw materials are complete, add dichloroethane and water for extraction, then add alkali solution to adjust the pH to neutral, separate the liquids, dehydrate and desolventize, and obtain 20.6 g of compound 3-nitro-2,5-dichlorobenzonitrile, with a yield of 95%;

[0091] The product 3-nitro-2,5-dichlorobenzonitrile from the previous step was added to a four-necked bottle, and 60 g of DMF and 10 g of xylene and 7.2 g of potassium fluoride were added. The mixture was kept at 100° 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 desolventization, the mixture was transferred to an autoclave, and 60 g of methanol, 0.4 g of palladium carbon and 13.5 g of potassium carbonate were added to the autoclave. The mixture was kept at 50° C. and filled with hydrogen at 1.5 MPa. The reaction was continued for 5 h. After HPLC detection, the raw materials were complete, and the mixture was filtered and desolventized to obtain 9.3 g of compound 3-amino-2-fluorobenzonitrile. The two-step yield was 72%.

[0092] The product 3-amino-2-fluorobenzonitrile from the previous step was added to a four-necked bottle, and 60 g of ethanol and 1 ml of sulfuric acid were added. The reaction was refluxed for 6 h, and then desolventized to obtain 11.5 g of the compound 3-amino-2-fluorobenzoic acid ethyl ester, with a yield of 92%.

[0093] Example 2

[0094] The difference from Example 1 is that the compound 2-chloro-5-bromobenzonitrile replaces 2,5-dichlorobenzonitrile, and the other molar ratios remain unchanged. The reaction produces 11.9 g of the compound 3-amino-2-fluorobenzoic acid ethyl ester, with a total yield of 65%;

[0095] Example 3

[0096] The difference from Example 1 is that water replaces the solvent ethanol, and the other molar ratios remain unchanged. The reaction produces 9.2 g of the compound 3-amino-2-fluorobenzamide with a yield of 87%;

[0097] Example 4

[0098] The intermediate product 3-nitro-2,5-dichlorobenzonitrile (0.095 mol) was added into a four-necked flask, and 60 g of ethanol and 1 ml of sulfuric acid were added. The mixture was refluxed for 6 h, and then desolventized to obtain 21.3 g of the compound 3-amino-2-chlorobenzoic acid ethyl ester, with a yield of 85%.

[0099] Then, the product of the previous step, ethyl 3-amino-2-chlorobenzoate, was added to 55 g of N, N-dimethylacetamide (DMAC) and 10 g of toluene, and 7.0 g of potassium fluoride was added. The mixture was 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 desolventization, 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 desolventized to obtain 10.9 g of the compound ethyl 3-amino-2-fluorobenzoate, with a two-step yield of 74%.

[0100] Example 5

[0101] In a four-necked flask equipped with a mechanical stirrer, a thermometer, and a condenser, add 23 g of dichloroethane and 23.0 g of 1,4-dichloro-2-(dichloromethyl)-benzene (0.1 mol, 99%, purchased from Aladdin), keep warm at -5°C, add 11.6 g of nitric acid dropwise for nitration, stir and react for 3 hours, HPLC detects that the raw materials are complete, add dichloroethane and water for extraction, then add alkali solution to adjust the pH to neutral, separate the liquids, dehydrate and desolventize, and obtain 22 g of the compound 6-nitro-1,4-dichloro-2-(dichloromethyl)-benzene, with a yield of 80%;

[0102] The 6-nitro-1,4-dichloro-2-(dichloromethyl)-benzene obtained in the previous step was added to a four-necked bottle, and 66g of xylene and 10ml of formic acid water were added. The mixture was kept at 60°C for 6h. After the reaction of the raw materials was completed, the mixture was separated and then 6.3g of potassium fluoride was added for dehydration for 8h. After the reaction of the raw materials was completed, the solvent was removed and the mixture was transferred to an autoclave. 64g of dioxane, 0.35g of palladium carbon and 17.1g of potassium carbonate were added to the autoclave. The mixture was kept at 60°C and filled with hydrogen at 1.5MPa. The mixture was reacted for 6h. After HPLC detection of the completeness of the raw materials, the mixture was filtered and desolventized to obtain 6.4g of compound 3-amino-2-fluorobenzaldehyde with a yield of 58%.

[0103] Then add the product 3-amino-2-fluorobenzaldehyde from the previous step into a four-necked bottle, add 20g of ethylene dichloride, keep the temperature at 20°C, pass chlorine gas, wait for the raw materials to react, remove the solvent, and obtain 6.9g of the compound 3-amino-2-fluorobenzoyl chloride, with a yield of 86%;

[0104] Example 6

[0105] The difference from Example 5 is that the compound 1,4-dichloro-2-(dimethoxymethyl)-benzene replaces 1,4-dichloro-2-(dichloromethyl)-benzene, and the other molar ratios remain unchanged. The reaction produces 7.1 g of the compound 3-amino-2-fluorobenzaldehyde with a total yield of 51%;

[0106] Example 7

[0107] The difference from Example 5 is that sulfuric acid water replaces formic acid water, and other molar ratios remain unchanged. The reaction produces 3.9 g of compound 3-amino-2-fluorobenzaldehyde with a yield of 35%;

[0108] Example 8

[0109] The intermediate product 6-nitro-1,4-dichloro-2-(dichloromethyl)-benzene (0.08 mol) was added to a four-necked bottle, and 60 g of DMAC and 8 g of xylene and 6.8 g of potassium fluoride were added. The reaction was kept at 135° C. for 9 h. After the raw materials were reacted, the temperature was cooled to room temperature and the salt was filtered out. After desolventization, 62 g of methanol, 0.51 g of palladium carbon and 14.3 g of potassium carbonate were added. The temperature was kept at 60° C. and hydrogen was introduced at 1.8 MPa. The reaction was continued for 8 h. HPLC detected that the raw materials were complete, and the solvent was filtered and removed to obtain 11.0 g of the compound 3-amino-2-fluoro-1-(dichloromethyl)-benzene, with a two-step yield of 71%.

[0110] The product of the previous step was added to a four-necked bottle, and 10 ml of formic acid water was added. The mixture was kept at 60°C for 5 h. After the reaction of the raw materials was completed, ethyl acetate was added for extraction and desolventization to obtain 7.5 g of compound 3-amino-2-fluorobenzaldehyde with a yield of 95%.

[0111] Then, the raw materials from the previous step were added into a four-necked bottle, and 20 g of dichloroethane was added. The temperature was kept at 20° C., and chlorine gas was passed through. After the raw materials reacted completely, 8.6 g of the compound 3-amino-2-fluorobenzoyl chloride was obtained by desolventization, with a yield of 92%.

[0112] The preferred embodiments of the present invention are described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, the technical solution of the present invention can be subjected to a variety of simple modifications, including the combination of various technical features in any other suitable manner, and these simple modifications and combinations should also be regarded as the contents disclosed by the present invention and belong to the protection scope of the present invention.

Claims

1. A method for synthesizing a 3-amino-2-fluorobenzoyl derivative (Formula AV), characterized in that: Route Ⅰ: Or Route II: Wherein, R1, R2 are each independently selected from chlorine, bromine or iodine; R is selected from hydrogen, halogen, hydroxyl, amino, amine, alkoxy, heteroaryl, aryl.

2. The synthesis method according to claim 1, characterized in that A-III-a is hydrogenated to give A-IV-a.

3. The synthesis method according to claim 1, characterized in that A-IV-b is hydrogenated to give AV.

4. The synthesis method according to claim 1, characterized in that Compound A-V is prepared by subjecting compound A-IV-a to cyano hydrolysis reaction.

5. The synthesis method according to claim 1, characterized in that Compound A-IV-b is prepared by fluorination reaction of compound A-III-b.

6. The synthesis method according to any one of claims 1 to 5, characterized in that The compound of formula A-III-a is synthesized by the following route: wherein R1 and R2 are as defined in claims 1-5.

7. The synthesis method according to claim 6, characterized in that The compound of formula AI is reacted with a nitrating agent to prepare the compound A-II.

8. The synthesis method according to claim 6, characterized in that Compound A-II is reacted with a fluorination agent to obtain compound A-III-a.

9. The synthesis method according to any one of claims 1 to 5, characterized in that The A-III-b compound is synthesized by the following route: wherein R1 and R2 are as defined in claims 1-5.

10. The synthesis method according to claim 9, characterized in that The AI ​​compound and the nitrating agent undergo nitration reaction to prepare the A-II compound.

11. The synthesis method according to claim 10, characterized in that: Compound A-III-b is prepared by hydrolyzing the cyano group of compound A-II.

12. A method for synthesizing a compound of formula B-VI, characterized in that: Route A: or Route B: Wherein, R3 and R4 are each independently selected from chlorine, bromine or iodine; R5 and R6 are each independently selected from fluorine, chlorine, bromine or iodine and alkoxy.

13. The synthesis method according to claim 12, characterized in that: Compound B-III-a is subjected to hydrogenation reaction to prepare compound B-IV-a.

14. The synthesis method according to claim 12, characterized in that: The B-IV-a compound is hydrolyzed to prepare the BV compound.

15. The synthesis method according to claim 12, characterized in that: The BV compound is reacted with a chlorinating agent to prepare the B-VI compound.

16. The synthesis method according to claim 12, characterized in that: Compound B-III-b is reacted with a fluorination agent to prepare compound B-IV-b.

17. The synthesis method according to claim 12, characterized in that: Compound BV is prepared by hydrogenation of compound B-III-b.

18. The synthesis method according to any one of claims 12 to 17, characterized in that: The B-III-a compound is synthesized by the following synthetic route: Wherein, R3 and R4 are each independently selected from chlorine, bromine or iodine; R5 and R6 are each independently selected from fluorine, chlorine, bromine or iodine and alkoxy.

19. The synthesis method according to claim 18, characterized in that: Compound BI is reacted with a nitrating agent to obtain compound B-II.

20. The synthesis method according to claim 18, characterized in that: Compound B-II is subjected to fluorination reaction with a fluorination agent to prepare compound B-III-a.

21. The synthesis method according to any one of claims 12 to 17, characterized in that: The B-III-b compound is synthesized by the following synthetic route: Wherein, R3 and R4 are each independently selected from chlorine, bromine or iodine; R5 and R6 are each independently selected from fluorine, chlorine, bromine or iodine and alkoxy.

22. The preparation method according to claim 21, characterized in that: The B-II compound is hydrolyzed to obtain the B-III-b compound.

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