CN115894352A - Method for preparing pyridone compound and intermediate thereof - Google Patents

Method for preparing pyridone compound and intermediate thereof Download PDF

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CN115894352A
CN115894352A CN202111159217.3A CN202111159217A CN115894352A CN 115894352 A CN115894352 A CN 115894352A CN 202111159217 A CN202111159217 A CN 202111159217A CN 115894352 A CN115894352 A CN 115894352A
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reaction
acid
reagent
catalyst
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马明亮
黄明智
陈邦池
周君津
关保川
陈啸飞
张洪伟
盛秋菊
王君良
王志
盛业亮
苏叶华
刘晨光
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MAX (RUDONG) CHEMICALS CO LTD
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Abstract

The invention relates to a method for preparing pyridone compounds and an intermediate thereof, wherein the method uses a compound II, a compound III and a compound V as raw materials, and comprises the following steps: the compound II and the compound III are subjected to coupling reaction under the action of the catalyst 1 to prepare a compound IV; step two: reacting the compound IV with a compound V under the action of a diazotization reagent and a catalyst 2 to obtain a compoundVI; step three: reacting the compound VI under certain conditions to generate a compound VII; step four: and reacting the compound VII with a reagent 1, methylamine and a reagent 2 in sequence to obtain the pyridone compound I. The method provides a new method for preparing the pyridone compound, and has the following advantages: mild reaction conditions, little corrosion to equipment, little three wastes and high safety. Expressed by the reaction formula: the method comprises the following steps:
Figure DDA0003289472630000011
step two:
Figure DDA0003289472630000012
step three:
Figure DDA0003289472630000013
step four:

Description

Method for preparing pyridone compound and intermediate thereof
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a method for preparing a pyridone compound and an intermediate thereof.
Background
Pyridone compounds, e.g. 1-methyl-3-phenyl-5- (3-trifluoromethylphenyl) -1H-pyridin-4-one
Figure BDA0003289472620000011
Is a pre-emergence selective herbicide and can control most of water or underwater plants, in particular to some algae such as nutria algae, waterfoxtail algae and the like, thereby having very important function in the aspects of purification and ecological balance of lakes and ponds (US 4152136A, CN 112244026A). Moreover, 1-methyl-3-phenyl-5- (3-trifluoromethylphenyl) -1H-pyridin-4-one has a special control effect on cotton field weeds, namely nightshade (CN 108967428B, CN 110208457A), and also has a good control effect on annual weeds, such as chenopodium quinoa, purslane, barnyard grass and the like (CN 108967428B, CN 112244026A).
At present, the preparation methods of the pyridone compounds mainly comprise the following steps:
the ELI LILLY company, 1976, disclosed a process for the preparation of pyridone compounds. The method takes 3-trifluoromethylaniline as a raw material to prepare 1-methyl-3-phenyl-5- (3-trifluoromethylphenyl) -1H-pyridine-4-ketone through diazotization, alkylation, condensation, amidation and cyclization reactions (US 4264775). Expressed by the reaction formula:
Figure BDA0003289472620000012
the amidation reaction requires anhydrous operation, and the reagents (A), (B) and (C)
Figure BDA0003289472620000013
And intermediates (A), (B)
Figure BDA0003289472620000014
Chloroacetate esters and/or>
Figure BDA0003289472620000015
Enamine compounds, etc.) are unstable, difficult to scale up, and not suitable for industrial production.
The ELI LILLY company, 1977, disclosed another novel method for synthesizing pyridone compounds. The method takes 3-trifluoromethyl benzyl cyanide as a raw material, and performs a Claisen condensation reaction with ethyl phenylacetate to generate 1-phenyl-3-cyano-3- (3-trifluoromethyl phenyl) -2-acetone, and then performs a hydrolysis decarboxylation reaction in the presence of sulfuric acid to obtain the 1-phenyl-3- (3-trifluoromethyl phenyl) -2-acetone (Journal of the American Chemical Society (1954), 76,501-3, CN 101070278). The obtained 1-phenyl-3- (3-trifluoromethylphenyl) -2-acetone, sodium methoxide and ethyl formate form a sodium dienolate intermediate, and finally the sodium dienolate intermediate reacts with methylamine hydrochloride to form 1-methyl-3-phenyl-5- (3-trifluoromethylphenyl) -1H-pyridin-4-one (U.S. Pat. No. 4,74209). 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:
Figure BDA0003289472620000021
according to the method, defluorination side reaction is obvious in the process of cyano hydrolysis and decarboxylation, a large amount of hydrofluoric acid is generated to seriously corrode equipment, and a large amount of waste acid, waste salt and the like are generated at the same time; and the yield is low, and the total yield is about 40%. In US4174209, anhydrous condition is not needed for reaction with sodium methoxide, and the reaction condition is harsh; US4235619 uses highly toxic phosgene, which is harmful to the human body. In addition, the 3-trifluoromethyl phenylacetonitrile and ethyl phenylacetate used are expensive. In particular, 3-trifluoromethyl benzyl cyanide is difficult to prepare, and the preparation process involves chloromethylation Friedel-crafts reaction of trifluoromethyl benzene and sodium cyanide cyanidation (CN 1257888C). The yield of the first chloromethylation reaction is low (67%), and a large amount of waste acid is generated; the cyanidation reaction adopts a highly toxic raw material sodium cyanide, and the generated cyanide-containing wastewater is difficult to treat.
Figure BDA0003289472620000022
OCCIDENTAL CHEMICAL corporation disclosed a new method for preparing 1, 3-diphenylpropanones in 1979. The method takes 3-trifluoromethyl benzaldehyde as a raw material, and prepares a product through five steps of aldol condensation, epoxidation, chloroepoxy ring opening, benzyl reduction and alcohol oxidation (US 4212998). Expressed by the reaction formula:
Figure BDA0003289472620000031
the 3-trifluoromethyl benzaldehyde used as the raw material in the method is expensive and has long reaction route. Wherein, tin tetrachloride is used in the ring-opening reaction of the chloro-epoxy, and a large amount of metal-containing waste liquid is generated and is difficult to treat; expensive palladium-carbon catalyst is adopted for benzyl hydrogenation reduction; hydrogen peroxide used in the oxidation process has potential safety hazards; the oxidizing agent pyridinium chlorochromate (PCC) used in the last step of oxidation reaction has toxicity and great harm to human bodies and the environment.
Disclosure of Invention
Aiming at the defects in the prior art, the technical personnel of the invention provide a novel method for preparing the pyridone compound and an intermediate thereof, which have the advantages of mild reaction conditions, small corrosion to equipment, less three wastes and high safety.
The first purpose of the invention is to provide a novel method for preparing pyridone compounds, which uses the compound II
Figure BDA0003289472620000032
Compound III>
Figure BDA0003289472620000033
Compound V->
Figure BDA0003289472620000034
Preparing a pyridone compound I with a structural formula of: ->
Figure BDA0003289472620000035
Wherein R is 1 Is hydrogen, -CF 3 ；R 2 Is hydrogen, -CF 3 And R is 1 And R 2 Not being hydrogen or-CF at the same time 3 ；
EWG is-CN or-COR'; r' is amino OR OR 3 Said R is 3 Hydrogen, C1-C10 alkyl or C1-C10 substituted alkyl.
The method specifically comprises the following reaction steps:
the method comprises the following steps: the compound II and the compound III are subjected to coupling reaction under the action of the catalyst 1 to prepare a compound IV;
step two: reacting the compound IV with a compound V under the action of a diazotization reagent and a catalyst 2 to obtain a compound VI;
step three: reacting the compound VI to generate a compound VII;
step four: the compound VII reacts with a reagent 1, methylamine and a reagent 2 in sequence to obtain a pyridone compound I, which is represented by the following reaction formula:
Figure BDA0003289472620000041
wherein R is 1 、R 2 EWG is as defined above;
x is halogen, preferably chlorine, bromine, more preferably chlorine.
In the first step, the catalyst 1 is any one or more of organic amine or organic phosphine, preferably organic amine, and more preferably any one of DABCO, DMAP or DBU.
The molar ratio of compound II to compound III in step one is 1; the molar ratio of the compound II to the catalyst 1 is 1-10, preferably 1-5, more preferably 1-3.
The reaction in the first step is carried out in an organic solvent or water or a mixture thereof, wherein the organic solvent is a polar organic solvent, preferably an alcohol solvent, and more preferably methanol, ethanol or tert-butyl alcohol.
In the second step, the diazotization reagent comprises any one or more of alkali metal nitrite, nitrite esters, nitrosyl sulfuric acid and nitrous acid gas, preferably, the diazotization reagent is 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 compound; the metal is preferably copper, and the halogen is F, cl, br and I; concretely cuprous chloride, cuprous oxide and cupric sulfate;
the molar ratio of the compound IV to the compound V in the second step is 1-5, preferably 1-2; the molar ratio of the diazotizing agent to compound V is 1-2, preferably 1-1.5; the molar ratio of compound V to catalyst 2 is 5 to 100, preferably 10 to 100, 1, more preferably 10 to 50.
The reaction of compound IV to compound V is carried out in an organic solvent, which is a polar organic solvent, preferably a ketone solvent, more preferably acetone, or water or a mixture thereof.
Reaction of compound IV with compound V to produce compound VI, a protic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and the like, may be added to the reaction.
In the third step, the compound VI can be respectively prepared into a compound VII under the catalysis of acid or alkali 2 in the presence of alkali 1;
wherein the base 1 is an organic or 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 AlCl 3 、FeCl 3 、SbCl 5 、SnCl 4 、BCl 3 、TiCl 4 、ZnCl 2 、MgCl 2 Preferred Lewis acids are AlCl 3 、FeCl 3 、MgCl 2 (ii) a Or protic acids such as hydrofluoric acid, sulfuric acid, phosphoric acid, and the like; or an aluminum alkyl;
the base 2 is an organic base or an inorganic base, preferably any one or more of alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal carbonate and alkaline earth metal carbonate, such as any one or more of potassium hydroxide, sodium hydroxide, potassium carbonate and sodium carbonate.
The reaction for preparing the compound VII from the compound VI in the step three is carried out in an organic solvent or water or a mixture thereof, the organic solvent is polar or non-polar solvent or their mixture, preferably ketone, alcohol, or their mixture,One or more of nitrile solvents; ketone solvents, preferably C3-C9 ketone solvents, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, methyl hexanone, diacetone alcohol, and the like; alcohol solvent, preferably C1-C10 alcohol solvent, such as methanol, ethanol, n-propanol, isopropanol, butanol, octanol, ethylene glycol, propylene glycol, and glycerol; the nitrile solvent is preferably a C2-C8 nitrile solvent, specifically acetonitrile, propionitrile, butyronitrile, etc. The reagent 1 and the reagent 2 in the fourth step are respectively and independently
Figure BDA0003289472620000051
Wherein R is 4 Is C1-C10 alkyl, C6-C12 aryl, preferably methyl, ethyl, more preferably methyl;
R 5 is C1-C10 alkyl, C6-C12 aryl, preferably methyl, ethyl, phenyl, more preferably methyl.
The molar ratio of the reagent 1 to the compound VII in the fourth step is 1-2.5, preferably 1-2.1; the molar ratio of methylamine to compound VII is 1-2, preferably 1.2-1.6; the molar ratio of reagent 2 to compound VII is 1-1.5, preferably 1-1.3
The reaction for preparing the pyridone compound I from the compound VII in the step four is carried out under the condition of no solvent or solvent, wherein the solvent is aromatic hydrocarbon, alcohol or chlorohydrocarbon, and preferably no solvent, toluene or ethanol.
The second purpose of the invention is to provide a new compound VI
Figure BDA0003289472620000061
Wherein R is 1 、R 2 X and EWG are as defined above.
The substituted alkyl group in the invention refers to an alkyl group which contains one or more substituent groups substituted for hydrogen atoms, wherein the substituent groups are atoms or functional groups. For example, substituents that may be present include, but are not limited to: alkyl, aryl, heteroaryl, halo, cyano, nitro, carbonyl, and the like.
Compared with the prior art, the invention has the remarkable technical effects that:
1. the method uses cheap and easily-obtained stable compounds such as aniline, benzaldehyde and acrylic acid as basic raw materials, and has low overall production cost through a new carbon skeleton construction strategy;
2. the whole process does not need to be operated without water, the reaction condition is mild, the use of sulfuric acid at high temperature is avoided, and special reaction equipment is not needed;
3. the use of highly toxic reagents such as phosgene, sodium cyanide, pyridinium chlorochromate (PCC) and the like is avoided, the generation of toxic, harmful and highly corrosive hydrogen fluoride gas is avoided, and the process safety is high;
4. the method has the advantages of high atom economy, great reduction of ammonia nitrogen wastewater, less three wastes and contribution to industrial production.
Detailed Description
The following examples further illustrate some of the features of the present invention, but the invention is not limited in its content and scope by the following examples.
Example 1 preparation of 1- (hydroxy (phenyl) methyl) acrylonitrile
To a reaction flask, 21.2g of benzaldehyde, 11.6g of acrylonitrile, 4.48g of dabco, and 20g of a tert-butanol-water mixed solvent (tert-butanol: water = 1) were added, and the mixture was stirred and mixed uniformly. Controlling the temperature of the reaction solution to be 0-30 ℃, and stirring until the reaction is finished. The reaction solution is acidified, layered and desolventized by an organic phase to obtain 30.85g of 2- (hydroxy (phenyl) methyl) acrylonitrile with a yield of 97%.
Example 1 preparation of methyl 2- (hydroxy (phenyl) meth) acrylate
106g of benzaldehyde, 94.6g of methyl acrylate and 56g of DABCO were added to a reaction flask, and 100g of a methanol-water mixed solvent (methanol: water = 70) was added and mixed uniformly with stirring. Controlling the temperature of the reaction solution to be 0-30 ℃, and stirring until the reaction is finished. The reaction solution is acidified, layered and desolventized by an organic phase to obtain 192g of the product methyl 2- (hydroxy (phenyl) methyl) acrylate with the yield of 98.7 percent.
Example 1 preparation of 3-ethyl 2- (hydroxy (phenyl) meth) acrylate
106g of benzaldehyde, 110g of ethyl acrylate and 56g of DABCO are added into a reaction bottle, 100g of methanol is added, and the mixture is stirred and mixed uniformly. Controlling the temperature of the reaction solution to be 0-30 ℃, and stirring until the reaction is finished. The reaction solution is acidified, layered and desolventized by an organic phase to obtain 197g of 2- (hydroxy (phenyl) methyl) ethyl acrylate with the yield of 96%.
Examples 1-4 preparation of methyl 2- (hydroxy (phenyl) meth) acrylate
106g of benzaldehyde, 94.6g of methyl acrylate and 61g of DMAP were added to a reaction flask, and 100g of a methanol-water mixed solvent (methanol: water = 70). Controlling the temperature of the reaction solution to be 0-30 ℃, and stirring until the reaction is finished. The reaction solution was acidified, layered and desolventized in organic phase to obtain 173g of methyl 2- (hydroxy (phenyl) methyl) acrylate with a yield of 90%. Examples 1-5 preparation of methyl 2- (hydroxy (phenyl) meth) acrylate
106g of benzaldehyde, 94.6g of methyl acrylate and 76g of DBU were added to a reaction flask, and 100g of a methanol-water mixed solvent (methanol: water = 70). Controlling the temperature of the reaction liquid to be 0-30 ℃, and stirring until the reaction is finished. The reaction solution was acidified, layered and desolventized with an organic phase to obtain 182g of methyl 2- (hydroxy (phenyl) methyl) acrylate with a yield of 95%. Examples 1-6 preparation of methyl 2- (hydroxy (phenyl) meth) acrylate
106g of benzaldehyde, 94.6g of methyl acrylate and 115g of trimethylamine are added into a reaction bottle, 100g of methanol is added, and the mixture is stirred and mixed uniformly. Controlling the temperature of the reaction solution to be 0-30 ℃, and stirring until the reaction is finished. The reaction solution is acidified, layered and desolventized by an organic phase to obtain 184.9g of 2- (hydroxy (phenyl) methyl) acrylate with the yield of 96.3 percent.
Examples 1-7 preparation of methyl 2- (hydroxy (phenyl) meth) acrylate
106g of benzaldehyde, 94.6g of methyl acrylate and 61g of DMAP were charged into a reaction flask, and 100g of a dioxane water mixed solvent (dioxane: water = 20) was added thereto, followed by stirring and mixing uniformly. Controlling the temperature of the reaction solution to be 0-30 ℃, and stirring until the reaction is finished. The reaction solution was acidified, layered and desolventized with an organic phase to obtain 186.6g of methyl 2- (hydroxy (phenyl) methyl) acrylate with a yield of 97.2%.
Examples 1-8 preparation of 2- (hydroxy (phenyl) methyl) acrylamide
106g of benzaldehyde, 78.2g of acrylamide and DABCO61g are added into a reaction bottle, 100g of a methanol-water mixed solvent (methanol: water = 70). Controlling the temperature of the reaction liquid to be 0-30 ℃, and stirring until the reaction is finished. The reaction solution is acidified, layered and desolventized by an organic phase to obtain 123.9g of the product 2- (hydroxy (phenyl) methyl) acrylamide with the yield of 70 percent.
Example 2 preparation of 1-2-chloro-3-hydroxy-3-phenyl-2- (3- (trifluoromethyl) benzyl) propionic acid
17.8g of 2- (hydroxy (phenyl) methyl) acrylic acid, 36g of acetone, 16.1g of m-trifluoromethylaniline, and 0.2g of cuprous chloride were added to the reaction flask, and the mixture was stirred and mixed uniformly. Controlling the temperature of the reaction solution to be 0-30 ℃, dropwise adding 19g of sodium nitrite aqueous solution, and stirring until the reaction is finished. The aqueous layer was separated from the reaction mixture, and the organic layer was desolventized to obtain 25g of 2-chloro-3-hydroxy-3-phenyl-2- (3- (trifluoromethyl) benzyl) propionic acid in a yield of 70%.
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)
ESI-MS m/z:[M-H] - ＝357.09
Example 2 preparation of 2-chloro-3-hydroxy-3-phenyl-2- (3- (trifluoromethyl) benzyl) propionic acid
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 are added into a reaction flask, and the mixture is stirred and mixed uniformly. Controlling the temperature of the reaction solution to be 0-30 ℃, dropwise adding 19g of sodium nitrite aqueous solution, and stirring until the reaction is finished. The aqueous layer was separated from the reaction mixture, and the organic layer was desolventized to give 14.6g of 2-chloro-3-hydroxy-3-phenyl-2- (3- (trifluoromethyl) benzyl) propionic acid in 68.4% yield.
EXAMPLE 2 preparation of 3-2-chloro-3-hydroxy-3-phenyl-2- (3- (trifluoromethyl) benzyl) propionitrile
47.7g of 2- (hydroxy (phenyl) methyl) acrylonitrile, 96g of acetone, 48.3g of m-trifluoromethylaniline, and 3g of cuprous chloride were added to a reaction flask, and the mixture was stirred and mixed uniformly. The temperature of the reaction solution was controlled to 0-30 ℃, 113.8g (40% aqueous solution) of sodium nitrite solution was added dropwise, and the reaction was stirred until the reaction was completed. The aqueous layer was separated from the reaction mixture, and 75g of 2-chloro-3-hydroxy-3-phenyl-2- (3- (trifluoromethyl) benzyl) propionitrile was obtained after desolvation of the organic layer, with a yield of 74%.
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:[M-H] - ＝338.15
Example 2 preparation of methyl 4-2-chloro-3-hydroxy-3-phenyl-2- (3- (trifluoromethyl) benzyl) acrylate
38.4g of methyl 2- (hydroxy (phenyl) methyl) acrylate, 90g of acetone, 32.2g of m-trifluoromethylaniline, and 1g of cuprous chloride were added to a reaction flask, and the mixture was stirred and mixed uniformly. Controlling the temperature of the reaction solution to be 0-30 ℃, dropwise adding 60g of hydrochloric acid, dropwise adding a sodium nitrite water solution under the condition of heat preservation, and stirring until the reaction is finished. The aqueous layer was separated from the reaction mixture, and the organic layer was desolventized to obtain 51g of methyl 2-chloro-3-hydroxy-3-phenyl-2- (3- (trifluoromethyl) benzyl) acrylate in a yield of 68%.
1 HNMR(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).
ESI-MS m/z:[M-H] - ＝372.15
Example 2 preparation of ethyl 5-2-chloro-3-hydroxy-3-phenyl-2- (3- (trifluoromethyl) benzyl) acrylate
20.6g of ethyl 2- (hydroxy (phenyl) methyl) acrylate, 40g of acetone, 16.1g of m-trifluoromethylaniline, and 0.5g of cuprous chloride were added to the reaction flask, and the mixture was stirred and mixed uniformly. Controlling the temperature of the reaction solution to be 0-30 ℃, dropwise adding 30g of hydrochloric acid, dropwise adding 17.3g of sodium nitrite aqueous solution under the condition of heat preservation, and stirring until the reaction is finished. Separating the reaction solution to obtain an aqueous layer, and desolventizing an organic layer to obtain 27g of ethyl 2-chloro-3-hydroxy-3-phenyl-2- (3- (trifluoromethyl) benzyl) acrylate with the yield of 70 percent
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)
ESI-MS m/z:[M-H]-＝386.14
EXAMPLE 2 preparation of 6-2-benzyl-2-chloro-3-hydroxy-3- (3-trifluoromethylphenyl) propionic acid
12.3g of 2- (hydroxy (3-trifluoromethyl-phenyl) methyl) acrylic acid, 25g of acetone, 4.6g of aniline and 0.1g of cuprous chloride are added into a reaction bottle, and the mixture is stirred and mixed uniformly. Controlling the temperature of the reaction solution to be 0-30 ℃, dropwise adding 15.2g of hydrochloric acid, dropwise adding 9.48g of sodium nitrite aqueous solution under the condition of heat preservation, and stirring until the reaction is finished. The aqueous layer was separated from the reaction mixture, and the organic layer was desolventized, purified and separated to give 13.46g of 2-benzyl-2-chloro-3-hydroxy-3- (3-trifluoromethylphenyl) propionic acid, yield 75.2%.
1 H NMR(500MHz,DMSO-d 6 )δ7.11–8.04(m,9H),5.41(s,1H),3.70(d,J＝13.8Hz,1H),2.47(d,J＝13.8Hz,1H).
EXAMPLE 3 preparation of 1-phenyl-3- (3- (trifluoromethyl) phenyl) propan-2-one
To a 500ml reaction flask were added 25g of 2-chloro-3-hydroxy-3-phenyl-2- (3- (trifluoromethyl) benzyl) propionic acid and 50g of methanol. 40g of an aqueous sodium hydroxide solution (30% aqueous solution) was added dropwise at 15-20 ℃. After stirring for 0.5h, the methanol was evaporated. 50g of toluene was added, the acid was adjusted, and the organic phase was separated. The organic phase was evaporated to remove toluene and diluted with 30g of DMF solvent. Then the solution is added dropwise to 5% MgCl which is preheated to 130-150 DEG C 2 In DMF solution, after the reaction is finished, 18.1g of 1-phenyl-3- (3- (trifluoromethyl) phenyl) propan-2-one is obtained with the yield of 93 percent.
EXAMPLE 3 preparation of 2-1-phenyl-3- (3- (trifluoromethyl) phenyl) propan-2-one
To a 500ml reaction flask were added 25g of 2-benzyl-2-chloro-3-hydroxy-3- (3-trifluoromethylphenyl) propionic acid and 50g of methanol, and 40g of an aqueous sodium hydroxide solution (30% aqueous solution) was added dropwise at 15 to 20 ℃. After stirring for 0.5h, the methanol was evaporated. 50g of toluene was added, the acid was adjusted, and the organic phase was separated. The organic phase was evaporated to remove toluene and diluted with 30g of DMF solvent. Then the solution is dripped into 5 percent AlCl which is preheated to 130-150 DEG C 3 In the solution of DMF, 17.5g of the product 1-phenyl-3- (3- (trifluoromethyl) phenyl) propan-2-one is obtained by post-treatment after the reaction is finished, and the yield is 90 percent.
EXAMPLE 4-1 preparation of 1-methyl-3-phenyl-5- (3-trifluoromethylphenyl) -1H-pyridin-4-one
At room temperature, 27.8g of 1-phenyl-3- (3-trifluoromethylphenyl) -2-acetone is dripped into 12.5g of N, N-dimethylformamide dimethyl acetal, the temperature is raised to 40-100 ℃ by stirring for reaction, the temperature is lowered after the reaction is finished, 10g of 40% methylamine water solution is added, the mixture is stirred for 4 hours, 30g of toluene is added, an organic layer is separated, 14g of N, N-dimethylformamide dimethyl acetal is added, the temperature is raised to 50-120 ℃ for reaction, the reaction is finished, and the product, namely the 1-methyl-3-phenyl-5- (3-trifluoromethylphenyl) -1H-pyridin-4-one, is obtained by washing, desolventizing and drying, 27.5g of the product, namely the 1-methyl-3-phenyl-5- (3-trifluoromethylphenyl) -1H-pyridin-4-one, and the yield is 82%.
EXAMPLE 4-2 preparation of 1-methyl-3-phenyl-5- (3-trifluoromethylphenyl) -1H-pyridin-4-one
At room temperature, 27.8g of 1-phenyl-3- (3-trifluoromethylphenyl) -2-acetone is dripped into 1lg of N, N-dimethylformamide diethyl acetal, the temperature is increased to 40-100 ℃ by stirring for reaction, the temperature is reduced after the reaction is finished, 13.5g of 30 percent methylamine ethanol solution is added, the mixture is stirred until the reaction is finished, 18gN, N-dimethylformamide diethyl acetal is added, the temperature is increased to 50-120 ℃ for reaction, and after the reaction is finished, the product 1-methyl-3-phenyl-5- (3-trifluoromethylphenyl) -1H-pyridin-4-one 28g is obtained by desolventizing, washing and drying, and the yield is 82.5 percent.
Example 4-3 preparation of 1-methyl-3-phenyl-5- (3-trifluoromethylphenyl) -1H-pyridin-4-one 1-phenyl-3- (3-trifluoromethylphenyl) -2-propanone 27.8g was added dropwise to 64g of dimethyl N, N-dimethylformamide sulfate adduct. Stirring the mixture until the reaction is finished, adding 10g of 40% methylamine aqueous solution, stirring the mixture, adding 30g of toluene, separating an organic layer, adding 14gN, N-dimethylformamide dimethyl acetal, heating the mixture to 50-120 ℃ for reaction, washing the mixture with water, desolventizing the mixture, and drying the mixture to obtain 27.5g of the product 1-methyl-3-phenyl-5- (3-trifluoromethylphenyl) -1H-pyridin-4-one with the yield of 88%.

Claims (10)

1. A preparation method of pyridone compound I is characterized in that the raw material comprises compound II
Figure FDA0003289472610000011
Compound III>
Figure FDA0003289472610000012
Compound V->
Figure FDA0003289472610000013
The structural formula of the pyridone compound I is shown in the specification
Figure FDA0003289472610000014
Wherein R is 1 Is hydrogen, -CF 3 ；R 2 Is hydrogen, -CF 3 And R is 1 And R 2 Not being hydrogen or-CF at the same time 3 ；
EWG is-CN or-COR'; r' is amino OR OR 3 Said R is 3 Hydrogen, C1-C10 alkyl or C1-C10 substituted alkyl.
2. A process for the preparation of pyridone compounds I according to claim 1, comprising the steps of:
the method comprises the following steps: the compound II and the compound III are subjected to coupling reaction under the action of the catalyst 1 to prepare a compound IV;
step two: reacting the compound IV with a compound V under the action of a diazotization reagent and a catalyst 2 to obtain a compound VI;
step three: reacting the compound VI to generate a compound VII;
step four: the compound VII reacts with a reagent 1, methylamine and a reagent 2 in sequence to obtain a pyridone compound I, which is represented by the following reaction formula:
the method comprises the following steps:
Figure FDA0003289472610000021
step two:
Figure FDA0003289472610000022
step three:
Figure FDA0003289472610000023
step four:
Figure FDA0003289472610000024
wherein R is 1 、R 2 EWG is as defined in claim 1;
x is halogen.
3. The process for preparing pyridone compounds I according to claim 2, wherein X is chloro.
4. The method for preparing pyridone compounds I according to claim 2, wherein the catalyst 1 in the first step is any one of an organic amine or an organic phosphine, preferably an organic amine; the molar ratio of the compound II to the compound III is 1; the molar ratio of the compound II to the catalyst 1 is 1-10, preferably 1-5.
5. The process for producing pyridone compounds I according to claim 4, wherein the catalyst 1 is any of DABCO, DMAP, or DBU.
6. The method of claim 2, wherein the diazotizing agent in step two comprises one or more of alkali metal nitrite, nitrosyl sulfuric acid, and nitrous acid gas; the catalyst 2 is a metal salt; the molar ratio of the compound IV to the compound V is 1-5, preferably 1-2; the molar ratio of the diazotizing agent to compound V is 1-2, preferably 1-1.5; the molar ratio of compound V to catalyst 2 is 5 to 100, preferably 10 to 50.
7. The preparation method of pyridone compounds I according to claim 2, characterized in that in step three, compound VI is catalyzed by acid or base 2 in the presence of base 1 to prepare compound VII, wherein base 1 is an organic base or an inorganic base; the acid is Lewis acid or protonic acid or alkyl aluminum; the alkali 2 is organic alkali or inorganic alkali.
8. The preparation method according to claim 7, characterized in that the base 1 is alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal carbonate, alkaline earth metal carbonate, preferably alkali metal hydroxide; the Lewis acid is AlCl 3 、FeCl 3 、SbCl 5 、SnCl 4 、BCl 3 、TiCl 4 、ZnCl 2 、MgCl 2 Preferably AlCl 3 、FeCl 3 、MgCl 2 (ii) a The protonic acid is hydrofluoric acid, sulfuric acid and phosphoric acid; the alkali 2 is alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal alcoholate, alkali metal carbonate, alkaline earth metal carbonate, preferably potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate.
9. The process for preparing pyridone compounds I according to claim 2, wherein the reagent 1 and the reagent 2 are independently selected from the group consisting of
Figure FDA0003289472610000031
R 4 Is C1-C10 alkyl, C6-C12 aryl, R 5 Is C1-C10 alkyl, C6-C12 aryl; the molar ratio of the reagent 1 to the compound VII is 1-2.5, preferably 1-2.1; the molar ratio of the reagent 2 to the compound VII is 1-1.5, preferably 1-1.3; the molar ratio of methylamine to compound VII is 1-2, preferably 1.2-1.6.
10. A novel compound VI, characterized by the structural formula:
Figure FDA0003289472610000032
wherein R is 1 、R 2 X, EWG are as defined in the claims2。
CN202111159217.3A 2021-09-30 2021-09-30 Method for preparing pyridone compound and intermediate thereof Pending CN115894352A (en)

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US4235619A (en) * 1977-06-27 1980-11-25 Eli Lilly And Company Method of controlling aquatic weeds and algae
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US4212998A (en) * 1979-05-14 1980-07-15 Hooker Chemicals & Plastics Corp. 1-Phenyl-3-(3-trifluoromethylphenyl)-2-propanol and process for its production
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