A method for preparing pyridone compounds and intermediates thereof

Abstract

The present invention relates to a method for preparing pyridone compounds and intermediates thereof. The method uses compound II, compound III and compound V as raw materials, and comprises the following steps: step 1: compound II undergoes coupling reaction with compound III under the action of catalyst 1 to obtain compound IV; step 2: compound IV and compound V react under the action of a diazotizing agent and catalyst 2 to obtain compound VI; step 3: compound VI reacts under certain conditions to generate compound VII; step 4: compound VII reacts with reagent 1, methylamine and reagent 2 in sequence to obtain pyridone compound I. The method provides a new method for preparing pyridone compounds, which has the following advantages: mild reaction conditions, low corrosion to equipment, less three wastes and high safety. It is expressed as follows by a reaction formula: step 1: step 2: step 3: step 4:

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and specifically relates to a method for preparing pyridone compounds and intermediates thereof. Background Art

[0002] Pyridone compounds, such as 1-methyl-3-phenyl-5-(3-trifluoromethylphenyl)-1H-pyridin-4-one It is a pre-emergence selective herbicide that can control most surface or underwater plants, especially some algae, such as bladderwort and foxtail algae, and therefore plays a very important role in the purification and ecological balance of lakes and ponds (US4152136A, CN112244026A). In addition, 1-methyl-3-phenyl-5-(3-trifluoromethylphenyl)-1H-pyridin-4-one has a special control effect on cotton field weeds Solanum nigrum (CN108967428B, CN110208457A), and also has a good control effect on annual weeds such as quinoa, purslane, and barnyard grass (CN108967428B, CN112244026A).

[0003] At present, the preparation methods of pyridone compounds mainly include the following:

[0004] In 1976, ELI LILLY Company disclosed a method for preparing pyridone compounds. The method uses 3-trifluoromethylaniline as a raw material, and prepares 1-methyl-3-phenyl-5-(3-trifluoromethylphenyl)-1H-pyridin-4-one (US4264775) through diazotization, alkylation, condensation, amidation, and cyclization. The reaction formula is as follows:

[0005]

[0006] The amidation reaction of this method requires anhydrous operation, and the reaction reagents involved ( and intermediates ( Chloroacetate, Enamine compounds, etc.) are unstable, difficult to scale up, and are not suitable for industrial production.

[0007] In 1977, ELI LILLY Company disclosed another new method for synthesizing pyridone compounds. This method uses 3-trifluoromethylbenzyl acetonitrile as a raw material, and carries out a Claisen condensation reaction with ethyl phenylacetate to produce 1-phenyl-3-cyano-3-(3-trifluoromethylphenyl)-2-propanone, and then undergoes a hydrolysis and decarboxylation reaction in the presence of sulfuric acid to obtain 1-phenyl-3-(3-trifluoromethylphenyl)-2-propanone (Journal of the American Chemical Society (1954), 76, 501-3, CN101070278). The obtained 1-phenyl-3-(3-trifluoromethylphenyl)-2-propanone reacts with sodium methoxide and ethyl formate to produce a sodium dienolate intermediate, and finally the sodium dienolate intermediate reacts with methylamine hydrochloride to produce 1-methyl-3-phenyl-5-(3-trifluoromethylphenyl)-1H-pyridin-4-one (US4174209). In addition, US4235619 discloses a method for obtaining pyridone compounds by reacting 1-phenyl-3-(3-trifluoromethylphenyl)-2-propanone with DMF, phosgene and methylamine. The reaction formula is as follows:

[0008]

[0009] The defluorination side reaction is obvious during the cyano hydrolysis and decarboxylation reaction of the method, and a large amount of hydrofluoric acid is produced, which seriously corrodes the equipment. At the same time, a large amount of waste acid, waste salt, etc. are produced; and the yield is low, with a total yield of about 40%. US4174209 requires anhydrous conditions for the reaction with sodium methoxide, and the reaction conditions are harsh; US4235619 uses highly toxic phosgene, which is harmful to the human body. In addition, the 3-trifluoromethylbenzyl acetonitrile and ethyl phenylacetate used are expensive. In particular, 3-trifluoromethylbenzyl acetonitrile is difficult to prepare, and its preparation process involves the chloromethylation Friedel-Crafts reaction of trifluoromethylbenzene and the sodium cyanide cyanation reaction (CN1257888C). The first step of the chloromethylation reaction has a low yield (67%) and produces a large amount of waste acid; the cyanation reaction uses highly toxic raw material sodium cyanide, and the cyanide-containing wastewater produced is difficult to treat.

[0010]

[0011] In 1979, OCCIDENTAL CHEMICAL Company disclosed a new method for preparing 1,3-diphenylacetone compounds. The method uses 3-trifluoromethylbenzaldehyde as the raw material, and obtains the product through five steps of aldol condensation, epoxidation, chloroepoxy ring opening, benzyl reduction, and alcohol oxidation (US4212998). The reaction formula is as follows:

[0012]

[0013] The raw material 3-trifluoromethylbenzaldehyde used in this method is expensive and the reaction route is long. Among them, tin tetrachloride is used in the chloroepoxide ring-opening reaction, which produces a large amount of metal-containing waste liquid that is difficult to handle; the benzyl hydrogenation reduction uses an expensive palladium carbon catalyst; the hydrogen peroxide used in the oxidation process has safety hazards; the oxidant pyridinium chlorochromate (PCC) used in the last step of the oxidation reaction is toxic and has great harm to the human body and the environment. Summary of the invention

[0014] In view of the deficiencies in the prior art, the present invention provides a new method for preparing pyridone compounds and intermediates thereof with mild reaction conditions, low corrosion to equipment, less three wastes, and high safety.

[0015] The first object of the present invention is to provide a new method for preparing pyridone compounds, wherein the method comprises compound II Compound III Compound V As a raw material, a pyridone compound I is prepared, wherein the pyridone compound I has the structural formula

[0016] Among them, R 1 is hydrogen, -CF3; R 2 is hydrogen, -CF3, and R 1 With R 2 Not hydrogen or -CF3 at the same time;

[0017] EWG is -CN or -COR'; R' is amine or OR 3 , the R 3 It is hydrogen, C1-C10 alkyl or C1-C10 substituted alkyl.

[0018] Specifically include the following reaction steps:

[0019] Step 1: Compound II undergoes a coupling reaction with compound III under the action of catalyst 1 to obtain compound IV;

[0020] Step 2: Compound IV reacts with compound V in the presence of a diazotizing agent and catalyst 2 to obtain compound VI;

[0021] Step 3: Compound VI is reacted to generate compound VII;

[0022] Step 4: Compound VII reacts with reagent 1, methylamine and reagent 2 in sequence to obtain pyridone compound I, which is represented by the following reaction formula:

[0023]

[0024] Among them, R 1 , R 2 , EWG definition as above;

[0025] X is a halogen, preferably chlorine or bromine, more preferably chlorine.

[0026] The catalyst 1 in step 1 is any one or more of an organic amine or an organic phosphine, preferably an organic amine, and more preferably the catalyst is any one of DABCO, DMAP or DBU.

[0027] The molar ratio of compound II to compound III in step 1 is 1:0.5-2, more preferably 1:0.8-1.5; the molar ratio of compound II to catalyst 1 is 1-10:1, preferably 1-5:1, more preferably 1-3:1.

[0028] The reaction in step 1 is carried out in an organic solvent or water or a mixture thereof. The organic solvent is a polar organic solvent, preferably an alcohol solvent, more preferably methanol, ethanol, or tert-butanol.

[0029] The diazotizing agent in step 2 includes any one or more of alkali metal nitrites, nitrite esters, nitrosyl sulfuric acid, and nitrous acid gas. Preferably, the diazotizing agent is an alkali metal nitrite, and more preferably, the alkali metal nitrite is sodium nitrite; the catalyst 2 is a metal salt, preferably a metal halide, a metal oxide, or a metal acid; the metal is preferably copper, and the halogen is F, Cl, Br, or I; specifically, cuprous chloride, cuprous oxide, or copper sulfate;

[0030] In step 2, the molar ratio of compound IV to compound V is 1-5:1, preferably 1-2:1; the molar ratio of the diazotizing agent to compound V is 1-2:1, preferably 1-1.5:1; the molar ratio of compound V to catalyst 2 is 5-100:1, preferably 10-100:1, and more preferably 10-50:1.

[0031] The reaction of compound IV to compound V is carried out in an organic solvent or water or a mixture thereof. The organic solvent is a polar organic solvent, preferably a ketone solvent, and more preferably acetone.

[0032] In the reaction of compound IV with compound V to prepare compound VI, a protonic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, etc. may be added to the reaction.

[0033] In step 3, compound VI can be prepared from compound VII in the presence of base 1 or under the catalysis of acid or base 2;

[0034] Wherein the base 1 is an organic base or an inorganic base, preferably an alkali metal hydroxide, an alkaline earth metal hydroxide, an alkali metal alcoholate, an alkaline earth metal alcoholate, an alkali metal carbonate, an alkaline earth metal carbonate, preferably an alkali metal hydroxide, such as potassium hydroxide, sodium hydroxide, more preferably sodium hydroxide; the acid is a Lewis acid, such as AlCl3, FeCl3, SbCl5, SnCl4, BCl3, TiCl4, ZnCl2, MgCl2, preferably a Lewis acid is AlCl3, FeCl3, MgCl2; or a protonic acid, such as hydrofluoric acid, sulfuric acid, phosphoric acid, etc.; or an alkyl aluminum;

[0035] Base 2 is an organic base or an inorganic base, preferably any one or more of alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, and alkaline earth metal carbonates, such as any one or more of potassium hydroxide, sodium hydroxide, potassium carbonate, and sodium carbonate.

[0036] Step 3 The reaction of compound VI to prepare compound VII is carried out in an organic solvent or water or a mixture thereof, wherein the organic solvent is a polar or non-polar solvent or a mixture thereof, preferably one or more of ketones, alcohols, and nitrile solvents; ketone solvents are preferably C3-C9 ketone solvents, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, methyl hexanone, diacetone alcohol, etc.; alcohol solvents are preferably C1-C10 alcohol solvents, such as methanol, ethanol, n-propanol, isopropanol, butanol, octanol, ethylene glycol, propylene glycol, glycerol, etc.; nitrile solvents are preferably C2-C8 nitrile solvents, such as acetonitrile, propionitrile, butyronitrile, etc. Reagent 1 and reagent 2 described in step 4 are independently

[0037] Among them, R 4 is a C1-C10 alkyl group or a C6-C12 aryl group, preferably a methyl group or an ethyl group, more preferably a methyl group;

[0038] R 5 It is a C1-C10 alkyl group or a C6-C12 aryl group, preferably a methyl group, an ethyl group or a phenyl group, and more preferably a methyl group.

[0039] In step 4, the molar ratio of reagent 1 to compound VII is 1-2.5:1, preferably 1-2.1:1; the molar ratio of methylamine to compound VII is 1-2:1, preferably 1.2-1.6:1; the molar ratio of reagent 2 to compound VII is 1-1.5:1, preferably 1-1.3:1

[0040] Step 4: The reaction of compound VII to prepare pyridone compound I is carried out in the absence of solvent or with solvent, and the solvent is aromatic hydrocarbons, alcohols, chlorinated hydrocarbons, preferably no solvent, toluene, or ethanol.

[0041] The second object of the present invention is to provide a new compound VI

[0042]

[0043] Among them, R 1 , R 2 , X, EWG are defined as above.

[0044] The substituted alkyl group of the present invention refers to an alkyl group containing one or more substituents replacing hydrogen atoms, wherein the substituents are atoms or functional groups. For example, the substituents that may appear include, but are not limited to, alkyl, aryl, heteroaryl, halogen, cyano, nitro, carbonyl, etc.

[0045] Compared with the prior art, the present invention has significant technical effects:

[0046] 1. A new method for preparing pyridone compounds is provided. The method uses cheap and readily available stable compounds such as aniline, benzaldehyde and acrylic acid as basic raw materials, and adopts a new carbon skeleton construction strategy, with low overall production cost;

[0047] 2. The entire process does not require anhydrous operation, the reaction conditions are mild, high-temperature sulfuric acid is avoided, and no special reaction equipment is required;

[0048] 3. Avoid the use of highly toxic reagents such as phosgene, sodium cyanide, pyridinium chlorochromate (PCC), etc., avoid the generation of toxic and harmful highly corrosive hydrogen fluoride gas, and the process safety is high;

[0049] 4. This method has high atomic economy, greatly reduces ammonia nitrogen wastewater, reduces three wastes, and is conducive to industrial production. DETAILED DESCRIPTION

[0050] The following examples further illustrate some features of the present invention, but the content and scope of the present invention are not limited to the following examples.

[0051] Example 1-1 Preparation of 2-(Hydroxy(phenyl)methyl)acrylonitrile

[0052] Add 21.2g of benzaldehyde, 11.6g of acrylonitrile, 4.48g of DABCO, and 20g of a mixed solvent of tert-butyl alcohol and water (tert-butyl alcohol: water = 1:1) to the reaction bottle, and stir to mix evenly. Control the temperature of the reaction liquid to 0-30°C, and stir until the reaction is completed. After acidification, stratification, and organic phase desolventization, the reaction liquid is obtained to obtain 30.85g of the product 2-(hydroxy(phenyl)methyl)acrylonitrile, with a yield of 97%.

[0053] Example 1-2 Preparation of methyl 2-(hydroxy(phenyl)methyl)acrylate

[0054] Add 106g of benzaldehyde, 94.6g of methyl acrylate, 56g of DABCO to the reaction bottle, add 100g of methanol-water mixed solvent (methanol: water = 70:30), and stir to mix evenly. Control the temperature of the reaction liquid to 0-30°C and stir until the reaction is completed. After acidification, stratification, and organic phase desolventization, the reaction liquid is obtained to obtain 192g of methyl 2-(hydroxy(phenyl)methyl)acrylate, with a yield of 98.7%.

[0055] Example 1-3 Preparation of ethyl 2-(hydroxy(phenyl)methyl)acrylate

[0056] Add 106 g of benzaldehyde, 110 g of ethyl acrylate, 56 g of DABCO, and 100 g of methanol to the reaction bottle, and stir to mix evenly. Control the temperature of the reaction solution to 0-30°C, and stir until the reaction is completed. After acidification, stratification, and organic phase desolventization, the reaction solution is obtained to obtain 197 g of ethyl 2-(hydroxy(phenyl)methyl)acrylate, with a yield of 96%.

[0057] Example 1-4 Preparation of methyl 2-(hydroxy(phenyl)methyl)acrylate

[0058] Add 106g of benzaldehyde, 94.6g of methyl acrylate, 61g of DMAP to the reaction bottle, add 100g of methanol-water mixed solvent (methanol: water = 70:30), and stir to mix evenly. Control the temperature of the reaction solution to 0-30°C and stir until the reaction is completed. After acidification, stratification, and organic phase desolventization, the reaction solution is obtained to obtain 173g of the product 2-(hydroxy(phenyl)methyl)acrylate, with a yield of 90%. Example 1-5 Preparation of 2-(hydroxy(phenyl)methyl)acrylate

[0059] Add 106g of benzaldehyde, 94.6g of methyl acrylate, 76g of DBU to the reaction bottle, add 100g of methanol-water mixed solvent (methanol: water = 70:30), and stir to mix evenly. Control the temperature of the reaction solution to 0-30°C and stir until the reaction is completed. After acidification, stratification, and organic phase desolventization, the reaction solution is obtained to obtain 182g of the product 2-(hydroxy(phenyl)methyl)acrylate, with a yield of 95%. Example 1-6 Preparation of 2-(hydroxy(phenyl)methyl)acrylate

[0060] Add 106g of benzaldehyde, 94.6g of methyl acrylate, 115g of trimethylamine, and 100g of methanol to the reaction bottle, and stir to mix evenly. Control the temperature of the reaction solution to 0-30°C and stir until the reaction is completed. After acidification, stratification, and organic phase desolventization, the reaction solution is obtained to obtain 184.9g of methyl 2-(hydroxy(phenyl)methyl)acrylate, with a yield of 96.3%.

[0061] Example 1-7 Preparation of methyl 2-(hydroxy(phenyl)methyl)acrylate

[0062] Add 106g of benzaldehyde, 94.6g of methyl acrylate, 61g of DMAP to the reaction bottle, add 100g of dioxane water mixed solvent (dioxane: water = 20:80), and stir to mix evenly. Control the temperature of the reaction solution to 0-30°C and stir until the reaction is completed. After acidification, stratification, and organic phase desolventization, the reaction solution is obtained to obtain 186.6g of methyl 2-(hydroxy(phenyl)methyl)acrylate, with a yield of 97.2%.

[0063] Example 1-8 Preparation of 2-(Hydroxy(phenyl)methyl)acrylamide

[0064] Add 106g of benzaldehyde, 78.2g of acrylamide, 61g of DABCO to the reaction bottle, add 100g of methanol-water mixed solvent (methanol: water = 70:30), and stir to mix evenly. Control the temperature of the reaction liquid to 0-30°C and stir until the reaction is completed. After acidification, stratification, and organic phase desolventization, the reaction liquid is obtained to obtain 123.9g of the product 2-(hydroxy(phenyl)methyl)acrylamide, with a yield of 70%.

[0065] Example 2-1 Preparation of 2-chloro-3-hydroxy-3-phenyl-2-(3-(trifluoromethyl)benzyl)propionic acid

[0066] Add 17.8 g of 2-(hydroxy(phenyl)methyl)acrylic acid, 36 g of acetone, 16.1 g of m-trifluoromethylaniline, and 0.2 g of cuprous chloride to the reaction bottle and stir to mix evenly. Control the temperature of the reaction solution to 0-30°C, dropwise add 19 g of sodium nitrite aqueous solution, and stir until the reaction is completed. The reaction solution is separated into an aqueous layer, and the organic layer is desolvated to obtain 25 g of 2-chloro-3-hydroxy-3-phenyl-2-(3-(trifluoromethyl)benzyl)propionic acid, with a yield of 70%.

[0067] 1 HNMR (CDCl3, 500HZ, TMS) δ = 7.37-7.53 (m, 9H), 5.28 (s, 1H), 3.55 (d, J = 13.9Hz, 1H), 2.89 (d, J = 13.9Hz, 1H)

[0068] ESI-MS m / z:[MH] - =357.09

[0069] Example 2-2 Preparation of 2-chloro-3-hydroxy-3-phenyl-2-(3-(trifluoromethyl)benzyl)propionic acid

[0070] Add 11g of 2-(hydroxy(phenyl)methyl)acrylic acid, 20g of acetone, 10g of m-trifluoromethylaniline, 1.98g of copper sulfate, and 0.31g of sodium sulfite to the reaction bottle and stir to mix evenly. Control the temperature of the reaction solution to 0-30°C, add 19g of sodium nitrite aqueous solution dropwise, and stir until the reaction is completed. The reaction solution is separated into an aqueous layer, and the organic layer is desolvated to obtain 14.6g of 2-chloro-3-hydroxy-3-phenyl-2-(3-(trifluoromethyl)benzyl)propionic acid, with a yield of 68.4%.

[0071] Example 2-3 Preparation of 2-chloro-3-hydroxy-3-phenyl-2-(3-(trifluoromethyl)benzyl)propionitrile

[0072] Add 47.7 g of 2-(hydroxy(phenyl)methyl)acrylonitrile, 96 g of acetone, 48.3 g of m-trifluoromethylaniline, and 3 g of cuprous chloride to the reaction bottle and stir to mix evenly. Control the temperature of the reaction solution to 0-30°C, dropwise add 113.8 g of sodium nitrite solution (40% aqueous solution), and stir until the reaction is completed. The reaction solution is separated into an aqueous layer, and the organic layer is desolvated to obtain 75 g of 2-chloro-3-hydroxy-3-phenyl-2-(3-(trifluoromethyl)benzyl)propionitrile, with a yield of 74%.

[0073] 1HNMR(CDCl3,500HZ,TMS)δ7.43-7.76(m,9H),4.95(d,J=28.9Hz,1H),3.45(d,J=11.6HZ,1H),3.35(d,J=14.1Hz,1H),3.14(d,J=14.1Hz,1H)ESI-MS m / z:[MH] - =338.15

[0074] Example 2-4 Preparation of methyl 2-chloro-3-hydroxy-3-phenyl-2-(3-(trifluoromethyl)benzyl)acrylate

[0075] Add 38.4g of methyl 2-(hydroxy(phenyl)methyl)acrylate, 90g of acetone, 32.2g of m-trifluoromethylaniline, and 1g of cuprous chloride to the reaction bottle, and stir to mix evenly. Control the temperature of the reaction solution to 0-30°C, add 60g of hydrochloric acid dropwise, keep warm and add sodium nitrite aqueous solution dropwise, and stir until the reaction is completed. The reaction solution is separated into an aqueous layer, and the organic layer is desolvated to obtain 51g of methyl 2-chloro-3-hydroxy-3-phenyl-2-(3-(trifluoromethyl)benzyl)acrylate, with a yield of 68%.

[0076] 1HNMR (CDCl3, 500HZ, TMS) δ7.54-7.32 (m, 9H), 5.26 (d, J = 7.0Hz, 1H), 3.71 (s ,3H),3.53(d,J=13.9Hz,1H),3.02(d,J=7.2Hz,1H),2.86(d,J=13.9Hz,1H).

[0077] ESI-MS m / z:[MH] - =372.15

[0078] Example 2-5 Preparation of ethyl 2-chloro-3-hydroxy-3-phenyl-2-(3-(trifluoromethyl)benzyl)acrylate

[0079] Add 20.6g of ethyl 2-(hydroxy(phenyl)methyl)acrylate, 40g of acetone, 16.1g of m-trifluoromethylaniline, and 0.5g of cuprous chloride to the reaction bottle and stir to mix evenly. Control the temperature of the reaction solution to 0-30°C, add 30g of hydrochloric acid dropwise, add 17.3g of sodium nitrite aqueous solution dropwise while keeping warm, and stir until the reaction is completed. The reaction solution is separated into an aqueous layer, and the organic layer is desolvated to obtain 27g of ethyl 2-chloro-3-hydroxy-3-phenyl-2-(3-(trifluoromethyl)benzyl)acrylate, with a yield of 70%

[0080] 1 HNMR (CDCl3, 500HZ, TMS) δ = 7.43-7.18 (m, 9H), 5.18 (d, J = 7.0Hz, 1H), 4.08 (q, J = 7.1Hz, 2H), 3.44(d,J=13.9Hz,1H),3.05(d,J=7.1Hz,1H),2.80(d,J=14.0Hz,1H),1.09(t,J=7.2Hz,3H)

[0081] ESI-MS m / z: [MH]-=386.14

[0082] Example 2-6 Preparation of 2-benzyl-2-chloro-3-hydroxy-3-(3-trifluoromethylphenyl)propionic acid

[0083] Add 12.3g of 2-(hydroxy(3-trifluoromethyl-phenyl)methyl)acrylic acid, 25g of acetone, 4.6g of aniline, and 0.1g of cuprous chloride to the reaction bottle, and stir to mix evenly. Control the temperature of the reaction liquid to 0-30°C, add 15.2g of hydrochloric acid dropwise, and add 9.48g of sodium nitrite aqueous solution dropwise while keeping warm, and stir until the reaction is completed. The reaction liquid is separated into an aqueous layer, and the organic layer is desolventized and purified to obtain 13.46g of the product 2-benzyl-2-chloro-3-hydroxy-3-(3-trifluoromethylphenyl)propionic acid, with a yield of 75.2%.

[0084] 1H NMR (500MHz, DMSO-d6) δ7.11–8.04(m,9H),5.41(s,1H),3.70(d,J=13.8Hz,1H),2.47(d,J=13.8Hz,1H).

[0085] Example 3-1 Preparation of 1-phenyl-3-(3-(trifluoromethyl)phenyl)propan-2-one

[0086] Add 25g of 2-chloro-3-hydroxy-3-phenyl-2-(3-(trifluoromethyl)benzyl)propionic acid and 50g of methanol to a 500ml reaction bottle. Add 40g of sodium hydroxide aqueous solution (30% aqueous solution) dropwise at 15-20°C. After stirring for 0.5h, evaporate the methanol. Add 50g of toluene, adjust the acidity, and separate the organic phase. After evaporating the toluene from the organic phase, add 30g of DMF solvent to dilute. Then add the solution dropwise to a 5% MgCl2 / DMF solution preheated to 130-150°C. After the reaction is completed, treat to obtain the product 1-phenyl-3-(3-(trifluoromethyl)phenyl)propan-2-one 18.1g, with a yield of 93%.

[0087] Example 3-2 Preparation of 1-phenyl-3-(3-(trifluoromethyl)phenyl)propan-2-one

[0088] Add 25g of 2-benzyl-2-chloro-3-hydroxy-3-(3-trifluoromethylphenyl)propionic acid and 50g of methanol to a 500ml reaction bottle, and add 40g of sodium hydroxide aqueous solution (30% aqueous solution) dropwise at 15-20°C. After stirring for 0.5h, evaporate the methanol. Add 50g of toluene, adjust the acidity, and separate the organic phase. After evaporating the toluene from the organic phase, add 30g of DMF solvent to dilute. Then add the solution dropwise to a 5% AlCl3 / DMF solution preheated to 130-150°C. After the reaction is completed, treat to obtain the product 1-phenyl-3-(3-(trifluoromethyl)phenyl)propan-2-one 17.5g, with a yield of 90%.

[0089] Example 4-1 Preparation of 1-methyl-3-phenyl-5-(3-trifluoromethylphenyl)-1H-pyridin-4-one

[0090] At room temperature, 27.8 g of 1-phenyl-3-(3-trifluoromethylphenyl)-2-propanone was added dropwise to 12.5 g of N,N-dimethylformamide dimethyl acetal, and the mixture was stirred and heated to 40-100°C for reaction. After the reaction, the mixture was cooled and 10 g of 40% methylamine aqueous solution was added. The mixture was stirred for 4 h, 30 g of toluene was added, the organic layer was separated, 14 g of N,N-dimethylformamide dimethyl acetal was added, the mixture was heated to 50-120°C for reaction, the reaction was completed, the mixture was washed with water, desolventized, and dried to obtain 27.5 g of the product 1-methyl-3-phenyl-5-(3-trifluoromethylphenyl)-1H-pyridine-4-one with a yield of 82%.

[0091] Example 4-2 Preparation of 1-methyl-3-phenyl-5-(3-trifluoromethylphenyl)-1H-pyridin-4-one

[0092] At room temperature, 27.8 g of 1-phenyl-3-(3-trifluoromethylphenyl)-2-propanone was added dropwise to 16 g of N,N-dimethylformamide diethyl acetal, and the mixture was stirred and heated to 40-100°C for reaction. After the reaction, the mixture was cooled and 13.5 g of 30% methylamine ethanol solution was added and stirred until the reaction was completed. 18 g of N,N-dimethylformamide diethyl acetal was added and the mixture was heated to 50-120°C for reaction. After the reaction was completed, the mixture was desolventized, washed with water and dried to obtain 28 g of the product 1-methyl-3-phenyl-5-(3-trifluoromethylphenyl)-1H-pyridin-4-one with a yield of 82.5%.

[0093] Example 4-3 Preparation of 1-methyl-3-phenyl-5-(3-trifluoromethylphenyl)-1H-pyridin-4-one 27.8 g of 1-phenyl-3-(3-trifluoromethylphenyl)-2-propanone was added dropwise to 64 g of N,N-dimethylformamide dimethyl sulfate adduct. After stirring until the reaction was completed, 10 g of 40% methylamine aqueous solution was added, stirred, 30 g of toluene was added, the organic layer was separated, 14 g of N,N-dimethylformamide dimethyl acetal was added, the temperature was raised to 50-120°C for reaction, the reaction was completed, washed with water, desolventized, and dried to obtain 27.5 g of the product 1-methyl-3-phenyl-5-(3-trifluoromethylphenyl)-1H-pyridin-4-one, with a yield of 88%.

Claims

1. A method for preparing a pyridone compound I, characterized in that: The method comprises the following steps: Step 1: Compound II undergoes a coupling reaction with compound III under the action of catalyst 1 to obtain compound IV; Step 2: Compound IV reacts with compound V in the presence of a diazotizing agent and catalyst 2 to obtain compound VI; Step 3: Compound VI is reacted to generate compound VII; Step 4: Compound VII reacts with reagent 1, methylamine and reagent 2 in sequence to obtain pyridone compound I, which is represented by the following reaction formula: Step 1: Step 2: Step 3: Step 4: Among them, R 1 is hydrogen, -CF3; R 2 is hydrogen, -CF3, and R 1 With R 2 Not the same; EWG is -CN or -COR'; R' is amine or OR 3 , the R 3 is hydrogen, C1-C10 alkyl; X is a halogen; The catalyst 1 is any one of an organic amine or an organic phosphine; The diazotizing agent includes any one or more of alkali metal nitrite, nitrite ester, nitrosyl sulfuric acid, and nitrous acid gas; The catalyst 2 is a metal salt, and the metal is copper; In step 3, compound VI is reacted in the presence of base 1 and then catalyzed by acid or base 2 to prepare compound VII, wherein the base 1 is an alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal carbonate, or alkaline earth metal carbonate; The acid is a Lewis acid or a protonic acid; the Lewis acid is AlCl3, FeCl3, SbCl5, SnCl4, BCl3, TiCl4, ZnCl2, MgCl2; the protonic acid is hydrofluoric acid, sulfuric acid, phosphoric acid; The base 2 is any one or more of alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal alcoholate, alkali metal carbonate, and alkaline earth metal carbonate; Reagent 1 described in step 4 is Reagent 2 is R 4 is a C1-C10 alkyl group, a C6-C12 aryl group, R 5 It is a C1-C10 alkyl group or a C6-C12 aryl group.

2. The method for preparing the pyridone compound I according to claim 1, characterized in that: The X is chlorine.

3. The method for preparing the pyridone compound I according to claim 1, characterized in that: The catalyst 1 described in step 1 is an organic amine; the molar ratio of the compound II to the compound III is 1:0.5-2; the molar ratio of the compound II to the catalyst 1 is 1-10:

1.

4. The method for preparing the pyridone compound I according to claim 3, characterized in that: The molar ratio of the compound II to the compound III is 1:0.8-1.5; the molar ratio of the compound II to the catalyst 1 is 1-5:

1.

5. The method for preparing the pyridone compound I according to claim 4, characterized in that: The catalyst 1 is any one of DABCO, DMAP or DBU.

6. The method for preparing the pyridone compound I according to claim 1, characterized in that: The molar ratio of compound IV to compound V is 1-5:1; the molar ratio of diazotizing agent to compound V is 1-2:1; and the molar ratio of compound V to catalyst 2 is 5-100:

1.

7. The method for preparing the pyridone compound I according to claim 6, characterized in that: The molar ratio of compound IV to compound V is 1-2:1; the molar ratio of diazotizing agent to compound V is 1-1.5:1; and the molar ratio of compound V to catalyst 2 is 10-50:

1.

8. The preparation method according to claim 1, characterized in that: The base 1 is an alkali metal hydroxide; the Lewis acid is AlCl3, FeCl3, MgCl2; and the base 2 is potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate.

9. The method for preparing the pyridone compound I according to claim 1, characterized in that: The molar ratio of reagent 1 to compound VII is 1-2.5:1; the molar ratio of reagent 2 to compound VII is 1-1.5:1; and the molar ratio of methylamine to compound VII is 1.2-1.6:

1.

10. The method for preparing the pyridone compound I according to claim 9, characterized in that: The molar ratio of reagent 1 to compound VII is 1-2.1:1; the molar ratio of reagent 2 to compound VII is 1-1.3:1; and the molar ratio of methylamine to compound VII is 1.2-1.6:

1.

11. A new compound VI, characterized in that Its structural formula is as follows: Among them, R 1 is hydrogen, -CF3; R 2 is hydrogen, -CF3, and R 1 With R 2 Not the same; EWG is -CN or -COR'; R' is amine or OR 3 , the R 3 It is hydrogen or C1-C10 alkyl.

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