A method for preparing 1-aryl-3-substituted acetone compounds and intermediates

Abstract

The present invention provides a novel method for preparing 1-aryl-3-substituted acetone compounds and intermediates. The method uses cheap and readily available aromatic amine raw materials, avoids the use of toxic and harmful reagents in the prior art, has simple process operation, does not require special equipment, is simple to separate and purify products, and is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and specifically relates to a method for preparing 1-aryl-3-substituted acetone compounds and intermediates. Background Art

[0002] 1-Aryl-3-substituted acetone compounds 1 are an important class of organic compounds.

[0003]

[0004] Some special 1-aryl-3-substituted acetone compounds have good biological activity. For example, patent CN110478338A reported that butyrolactone metabolite ketone (compound A) has good therapeutic effect on preventing and treating hyperlipidemia.

[0005]

[0006] 1-Aryl-3-substituted acetone compounds are also an important class of organic synthesis intermediates. For example, 1-Aryl-3-substituted acetone compounds can be used as intermediates to prepare hypoglycemic drugs (CN110002975A), choleretic drugs such as choleretics, anti-epileptic drugs such as methyltoin (CN107118086A); they can also be used to prepare pesticides such as sodium diphacin (CN107118086A); and can be used to prepare photoelectric crystal conductor materials (CN110002975A).

[0007] In addition, 1-aryl-3-substituted acetone compounds can also be used to prepare high-aromatic ring polymers. These polymers have high molecular weight, good solubility in organic solvents, good film-forming properties, high glass transition temperature and high thermal decomposition temperature, and therefore play a very important role in the fields of aviation, aerospace, electronics, machinery, etc. (CN101100420B).

[0008] There are six main methods for synthesizing 1-aryl-3-substituted acetone compounds.

[0009] The first method for preparing 1-aryl-3-substituted acetone compounds is to use phenylacetic acid as a raw material, DCC (dicyclohexylcarbodiimide) as a dehydrating agent, and DMAP as a catalyst for condensation (CN109942389A; CN110041182A), with a yield of 55%-75%; the reaction equation is as follows:

[0010]

[0011] The reaction conditions of this method are mild, but a large amount of 1,3-dicyclohexylurea is produced, and the catalyst DMAP used is expensive. In addition, when the asymmetric product is prepared by this method, a cross-condensation side reaction occurs, and the product needs to be separated by column chromatography, which is not suitable for industrial production.

[0012] The second method for preparing 1-aryl-3-substituted acetone compounds is to use phenylacetic acid ester as raw material and sodium hydrogen as base to carry out Claisen condensation reaction. The generated β-ketoester intermediate is hydrolyzed and decarboxylated in acetic acid and hydrochloric acid at high temperature (Synthesis 2011 (17): 2721-2723), and the yield is 86%. The reaction formula is as follows:

[0013]

[0014] The reaction uses sodium hydrogen as a base, which produces hydrogen byproducts, which is a serious safety hazard. At the same time, the hydrolysis and decarboxylation reaction takes a long time, has high temperatures, and is highly corrosive to equipment. When this method is used to prepare asymmetric compounds, cross-condensation byproducts are produced, making it difficult to separate and purify the products.

[0015] The third method for preparing 1-aryl-3-substituted acetone compounds is to react halogen-substituted aromatic chlorides with p-toluenesulfonylmethyl isocyanide to prepare the target compound (CN110002975A), with a yield of 60%. The reaction formula is as follows:

[0016]

[0017] This method requires the use of isocyanide, and the reaction has a foul odor and is toxic; the product needs to be separated and purified by column chromatography, and is not suitable for industrial production; in addition, this method is only suitable for the preparation of symmetrical 1-aryl-3-substituted acetone compounds.

[0018] The fourth method for preparing 1-aryl-3-substituted acetone compounds is to use benzyl halide as a raw material, and to obtain the target product by reacting a Grignard reagent with an ester (CN109796317A); the reaction formula is as follows:

[0019]

[0020] In the method, anhydrous lithium chloride needs to be added to form a stable and less active benzyl magnesium lithium chloride when preparing the Grignard reagent, so as to avoid the self-condensation side reaction of the benzyl halide. Although this method can be effectively used to prepare asymmetric 1-aryl-3-substituted acetone compounds, the Grignard reaction conditions are harsh (anhydrous and oxygen-free), and the 1-aryl-3-substituted acetone and the Grignard reagent will further add to obtain a tertiary alcohol byproduct (Journal of the Indian Chemical Society, 85(3), 300-305; 2008); and the reaction raw materials are expensive, which is not suitable for industrial production.

[0021] The fifth method for preparing 1-aryl-3-substituted acetone compounds is to use substituted benzaldehyde and acetophenone as raw materials, and obtain the target product through five steps of aldol condensation, epoxidation, chloroepoxy ring opening, benzyl reduction, and alcohol oxidation to ketone (US4212998A), and the five-step yield is 39.5%; the reaction formula is as follows:

[0022]

[0023] 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 epoxidation process has safety hazards; the oxidant pyridinium chlorochromate (PCC) used in the last step of the oxidation reaction is toxic and harmful to the human body.

[0024] The sixth method for preparing 1-aryl-3-substituted acetone compounds is to use 3-trifluoromethylbenzyl acetonitrile as a raw material, sodium alcoholate as a base and ethyl phenylacetate to carry out a Claisen type condensation reaction, and the β-ketocyanide obtained by the condensation is hydrolyzed in a dilute sulfuric acid aqueous solution to obtain the target compound (CN100558690C), with a total yield of 62-63%; the reaction formula is as follows:

[0025]

[0026] The method uses benzyl cyanide as a raw material, and better solves the Claisen ester self-condensation side reaction (ethyl phenylacetate self-condensation). However, benzyl cyanide, especially substituted benzyl cyanide, is difficult to prepare and expensive. For example, the preparation method of m-trifluoromethyl benzyl cyanide is to obtain m-trifluoromethyl benzene through Friedel-Crafts reaction and cyanidation reaction (CN1257888C). The Friedel-Crafts reaction yield is low (67%), and a large amount of waste acid is generated. The cyanidation reaction uses highly toxic raw material sodium cyanide, and the generated cyanide wastewater is difficult to treat, and the equipment material requirements are relatively high; the reaction cycle is long, the reaction yield is low, and the cost is high. Summary of the invention

[0027] In view of the deficiencies of the prior art, the present invention provides a new method for preparing 1-aryl-3-substituted acetone compounds and an intermediate thereof.

[0028] The first object of the present invention is to provide a method for preparing a 1-aryl-3-substituted acetone compound 1, wherein the method uses an epoxy carboxylic acid compound 2 or a salt 3 thereof as a raw material, and decarboxylates and rearranges the 1-aryl-3-substituted acetone 1 under the action of a catalyst 1, which is expressed as follows:

[0029]

[0030] in,

[0031] The R 1 is any one of hydrogen, unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted C6-C12 aryl, and unsubstituted or substituted heteroaryl;

[0032] When R 1 When it is an unsubstituted C6-C12 aryl group, it is preferably a phenyl group;

[0033] When R 1 When it is a substituted C6-C12 aryl group, it is preferably a substituted phenyl group, such as any one or more of a halogen-substituted C1-C10 alkyl group, wherein the halogen is any one or more of F, Cl, Br, and I;

[0034] When R 1 When it is an unsubstituted or substituted heteroaryl group, it is preferably any one of an unsubstituted or substituted heteroaryl group containing 1 to 4 atoms selected from nitrogen, oxygen and sulfur atoms, and more preferably an unsubstituted or substituted pyridyl group;

[0035] Ar is any one of an unsubstituted or substituted C6-C12 aryl group, an unsubstituted or substituted heteroaryl group containing 1 to 4 atoms selected from nitrogen, oxygen, and sulfur atoms;

[0036] Preferably, Ar is phenyl or Any of the following:

[0037] When Ar is n is an integer from 1 to 5, such as 1, 2, 3, 4, 5; when n is an integer not less than 2, multiple R 2 Can be the same or different;

[0038] R 2 is one or more selected from halogen, cyano, nitro, unsubstituted or substituted alkyl, unsubstituted or substituted amino; preferably one or more selected from unsubstituted or substituted C1-C10 alkyl;

[0039] More preferably, n is 1; R 2 Any one or more of halogen-substituted C1-C10 alkyl, wherein the halogen is F, Cl, Br, or I;

[0040] When Ar is a heteroaryl group, it is preferably any one of unsubstituted or substituted heteroaryl groups containing 1 to 4 atoms selected from nitrogen, oxygen and sulfur atoms, and more preferably an unsubstituted or substituted pyridyl group.

[0041] The M is an ammonium ion, an alkali metal ion, or an alkaline earth metal ion;

[0042] When M is an ammonium ion or an alkali metal ion, m is 1;

[0043] When M is an alkaline earth metal ion, m is 2;

[0044] The ammonium ion may be

[0045] R 6 -R 9 Each of them is independently H, unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted heterocycloalkyl containing nitrogen, oxygen and sulfur atoms, and unsubstituted or substituted C6-C12 aryl;

[0046] Y can be any of C, N, O, and S;

[0047] p is any integer between 0 and 2, such as 0, 1, 2;

[0048] The ammonium ion is When

[0049] The ammonium ion is When

[0050] When M is an alkali metal ion, it is preferably a sodium ion;

[0051] When M is an alkaline earth metal ion, it is preferably a calcium ion;

[0052] The above-mentioned ammonium ion is an unsubstituted or substituted ammonium ion.

[0053] The catalyst 1 is an acid or a base; the acid can be a proton acid, a Lewis acid, or an alkyl aluminum; the base can be an organic base or an inorganic base; the proton acid is hydrofluoric acid, sulfuric acid, or phosphoric acid; the Lewis acid is AlCl3, FeCl3, SbCl5, SnCl4, BCl3, TiCl4, ZnCl2, or MgCl2, preferably AlCl3, FeCl3, or MgCl2; the base can be an alkali metal hydroxide, an alkaline earth metal hydroxide, an alkali metal alcoholate, an alkaline earth metal alcoholate, an alkali metal carbonate, or an alkaline earth metal carbonate;

[0054] The reaction solvent may be a polar solvent, a non-polar solvent or a mixture thereof, preferably one or more of a C6-C12 aromatic hydrocarbon solvent, a C1-C10 alcohol solvent, a C1-C6 amide solvent or a C1-C6 (sulfoxide) sulfone solvent;

[0055] The C6-C12 aromatic hydrocarbon solvents include toluene, xylene, and trimethylbenzene;

[0056] The C1-C10 alcohol solvents include methanol, ethanol, n-propanol, isopropanol, butanol, octanol, ethylene glycol, propylene glycol, glycerol, etc.

[0057] The C1-C6 amide solvents include DMF, DMAC and NMP;

[0058] The C1-C6 (sub)sulfone solvents include DMSO and sulfolane;

[0059] The molar ratio of the raw material epoxy carboxylic acid compound 2 or its salt 3 to the catalyst 1 is 1:0.01-1, preferably 1:0.01-0.2;

[0060] The second object of the present invention is to provide an epoxy carboxylic acid compound 2 or a salt 3 thereof, the structural formula of which is as follows:

[0061]

[0062] Among them, Ar, R 1 , M, m are as defined above;

[0063] The third object of the present invention is to provide a method for preparing an epoxycarboxylic acid compound 2 or a salt thereof 3, the method comprising the following steps:

[0064] Step 1: Aromatic amine 4 reacts with a diazotizing agent to generate a diazonium salt, which then reacts with olefin 5 in the presence of a catalyst 2 to obtain an intermediate 6;

[0065] Step 2: Intermediate 6 reacts with alcohol 7 to prepare intermediate 8;

[0066] Step 3: Intermediate 8 reacts with aldehyde 9 under the action of base 1 to obtain intermediate 10;

[0067] Step 4: The intermediate 10 is hydrolyzed under the action of the base 2 to obtain the epoxycarboxylic acid compound 2; or further comprising

[0068] Step 5: epoxycarboxylic acid compound 2 is reacted with base 3 to obtain epoxycarboxylate 3; the equation is as follows:

[0069]

[0070] in,

[0071] Ar, R 1 , M, m are defined as above.

[0072] R 3 For cyano, COR 4 ;

[0073] R 4 is hydroxy, unsubstituted or substituted C1-C10 alkoxy, or amino;

[0074] R 5 is a C1-C10 alkyl group, preferably a methyl group or an ethyl group;

[0075] X is a halogen, such as F, Cl, Br, I;

[0076] In the first step, the diazotization agent includes any one or more of alkali metal nitrites, nitrite esters, nitrosyl sulfuric acid, and nitrous acid gas. Preferably, the diazotization agent is an alkali metal nitrite, and more preferably, the alkali metal nitrite is sodium nitrite.

[0077] The catalyst 2 is a metal salt, preferably a metal halide, a metal oxide, or a metal acidide; the metal is preferably copper, and the halogen is F, Cl, Br, or I; specifically, cuprous chloride, cuprous oxide, or cupric sulfate;

[0078] In the second step, the reaction is carried out under acidic conditions, and the acid is hydrochloric acid, hydrogen chloride, or sulfuric acid;

[0079] In the third step reaction, the base 1 is an alkali metal or alkaline earth metal hydroxide, an alkali metal or alkaline earth metal carbonate, an alkali metal or alkaline earth metal alcoholate, an alkali metal or alkaline earth metal hydride and a mixture thereof; preferably an alkali metal alcoholate, such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide;

[0080] In the fourth step reaction, the base 2 is an alkali metal or alkaline earth metal hydroxide, an alkali metal or alkaline earth metal carbonate, preferably an alkali metal hydroxide, such as potassium hydroxide, sodium hydroxide, more preferably sodium hydroxide.

[0081] In the fifth step reaction, the base 3 is an organic base or an inorganic base; the organic base is an amine compound, specifically triethylamine, cyclohexanediamine, pyridine, tetrahydropyrrole, hexahydropyridine, morpholine, triethylenediammonium (DABCO), diazabicyclo (DBU); the inorganic base is ammonia gas, ammonia water, alkali metal or alkaline earth metal hydroxide, alkali metal or alkaline earth metal carbonate, preferably sodium hydroxide or calcium hydroxide;

[0082] The preparation of epoxycarboxylic acid compound 2 can be prepared step by step from intermediate 8 or in one pot, that is, after obtaining intermediate 10, the product can be separated and then hydrolyzed to prepare epoxycarboxylic acid compound 2. Alternatively, the product can be directly hydrolyzed to prepare epoxycarboxylic acid compound 2 without separation, which is expressed as follows:

[0083]

[0084] Among them, Ar, R 1 , R 5 , X, base 1, and base 2 are as defined above.

[0085] The above-mentioned reactions can be carried out in an organic solvent, water or a mixture thereof, or in the absence of a solvent;

[0086] The first step reaction solvent is preferably an organic solvent or water, and the organic solvent is a polar organic solvent, preferably a ketone solvent, and more preferably acetone.

[0087] The second step reaction solvent is preferably an organic solvent or water, and the organic solvent is preferably an alcohol solvent, more preferably a C1-C10 alcohol solvent, such as methanol, ethanol, n-propanol, isopropanol, butanol, octanol, ethylene glycol, propylene glycol, glycerol, etc.

[0088] The solvent for the third step reaction is preferably an aromatic hydrocarbon solvent, an amide solvent, a (sub)sulfone solvent, or an alcohol solvent; the aromatic hydrocarbon solvent is preferably a C6-C12 aromatic hydrocarbon solvent, such as toluene, xylene, and trimethylbenzene; the amide solvent is preferably a C1-C6 amide solvent, such as DMF and DMAC; the (sub)sulfone solvent is preferably a C1-C6 (sub)sulfone solvent, such as DMSO and sulfolane; the alcohol solvent is preferably a C1-C10 alcohol solvent, such as methanol, ethanol, n-propanol, isopropanol, butanol, octanol, ethylene glycol, propylene glycol, glycerol, etc.;

[0089] The reaction solvent in the fourth step is preferably an aromatic hydrocarbon solvent, an amide solvent, a (sub)sulfone solvent, or an alcohol solvent; the aromatic hydrocarbon solvent is preferably a C6-C12 aromatic hydrocarbon solvent, such as toluene, xylene, and trimethylbenzene; the amide solvent is preferably a C1-C6 amide solvent, such as DMF and DMAC; the (sub)sulfone solvent is preferably a C1-C6 (sub)sulfone solvent, such as DMSO and sulfolane; the alcohol solvent is preferably a C1-C10 alcohol solvent, such as methanol, ethanol, n-propanol, isopropanol, butanol, octanol, ethylene glycol, propylene glycol, glycerol, etc.;

[0090] The fifth step reaction solvent is water or an organic solvent; the organic solvent is preferably a C1-C10 solvent, more preferably n-hexane.

[0091] Compared with the prior art, the present invention has the following significant features:

[0092] (1) The present invention provides a novel method for preparing 1-aryl-3-substituted acetone compounds, wherein the carbonyl carbon atom of the 1-aryl-3-substituted acetone compounds is derived from the C-2 carbon atom of cheap and readily available acrylic acid or its derivatives.

[0093] (2) The method for preparing 1-aryl-3-substituted acetone compounds provided by the present invention uses cheap and readily available aromatic amine raw materials, avoiding the use of toxic and harmful reagents such as tin tetrachloride, hydrogen peroxide, pyridinium chlorochromate (PCC), paraformaldehyde, sodium cyanide, p-toluenesulfonylmethyl isocyanide, etc. used in the prior art;

[0094] (3) The method for preparing 1-aryl-3-substituted acetone compounds provided by the present invention can be used to prepare symmetrical or asymmetrical 1-aryl-3-substituted acetone compounds, and is particularly suitable for preparing symmetrical 1-aryl-3-substituted acetone compounds;

[0095] (4) The method for preparing 1-aryl-3-substituted acetone provided by the present invention has simple process operation, does not require special equipment, and is easy to separate and purify the product, and is suitable for industrial production. DETAILED DESCRIPTION

[0096] 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.

[0097] Example 1: Synthesis of 2-chloro-3-(3-trifluoromethylphenyl)propionitrile

[0098] Add m-trifluoromethylaniline (100 g) to acetone, cool to 5-15°C, add 30% hydrochloric acid (181 g), and stir for 1 hour. Then add cuprous chloride (1 g), acrylonitrile (98 g), and begin to drop sodium nitrite aqueous solution (113 g). After the reaction is complete, concentrate, and let stand to separate to obtain 140 g of 2-chloro-3-(3-trifluoromethylphenyl)propionitrile, with a yield of 88%. 1 H NMR (500MHz, DMSO): δ7.89–7.52(m,4H), 5.61(t,J=7.1Hz,1H), 3.53(dd,J=14.0,7.0Hz,1H), 3.48(dd,J=14.0,7.3Hz,1H).

[0099] Example 2: Synthesis of 2-chloro-3-(3-trifluoromethylphenyl)propionic acid

[0100] Add m-trifluoromethylaniline (100g) to acetone, cool to 5-15°C, add 30% hydrochloric acid (181g), and stir for 1h. Then add (1g) cuprous chloride, acrylic acid (134g), and begin to drop sodium nitrite aqueous solution (140g). After the reaction is complete, stand still and separate the layers, concentrate the organic layer, extract and wash with water, and concentrate the organic phase. Purification gives 127g of 2-chloro-3-(3-trifluoromethylphenyl)propionic acid, with a yield of 80%. 1 H NMR (500MHz, DMSO): δ13.48 (s, 1H), 8.20–7.12 (m, 4H), 4.81 (dd, J = 8.3, 6.1Hz, 1H), 3.42 (dd, J = 14.2, 6.1Hz, 1H), 3.20 (dd, J = 14.2, 8.4Hz, 1H).

[0101] Example 3: Synthesis of methyl 2-chloro-3-(3-trifluoromethylphenyl)propionate

[0102] Add m-trifluoromethylaniline (100 g) to acetone, cool to 5-15°C, add hydrochloric acid (181 g), and stir for 1 hour. Then add cuprous chloride (1 g), methyl acrylate (160 g), and begin to dropwise add sodium nitrite aqueous solution (113 g). After the reaction is complete, concentrate, and let stand to separate to obtain 156 g of methyl 2-chloro-3-(3-trifluoromethylphenyl)propionate, with a yield of 85%. 1 H NMR (500MHz, DMSO): δ3.19–3.28 (dd, J=14.2, 8.5Hz, 1H), 3.40–3.49 (dd, J=14.2, 6.0Hz, 1H) ,3.68–3.71(s,3H),4.94–5.02(dd,J=8.5,6.0Hz,1H),7.52–7.65(m,3H),7.65–7.71(s,1H).

[0103] Example 4: Synthesis of 2-chloro-3-phenylpropionic acid

[0104] Add aniline (80 g) to acetone, cool to 5-15°C, add 30% hydrochloric acid (250 g), and stir for 1 hour. Then add cuprous chloride (0.8 g), acrylic acid (186 g), and begin to dropwise add sodium nitrite aqueous solution (163 g). After the reaction is complete, concentrate, extract, and concentrate the organic layer to obtain 143 g of 2-chloro-3-phenylpropionic acid with a yield of 81%. 1 H NMR (500MHz, DMSO): δ13.37(s,1H),7.34–7.27(m,4H),7.27–7.22(m,1H),4.69(d d, J=7.9, 6.7Hz, 1H), 3.31 (dd, J=14.1, 6.6Hz, 1H), 3.09 (dd, J=14.1, 8.0Hz, 1H).

[0105] Example 5: Synthesis of 2-chloro-3-phenylpropionamide

[0106] At 5-15°C, add aniline (46.4g) to a 30% hydrochloric acid aqueous solution (156g), then add water (208g) dropwise, and cool to -5-0°C. Add 40% sodium nitrite aqueous solution (95g) dropwise and stir. After the reaction is complete, the diazo solution is ready for use. In another reaction bottle, add acrylamide (178g) to acetone, cool to 10-20°C, and add cuprous chloride (4.0g). Add the reserved diazo solution dropwise. After the reaction is complete, concentrate, add toluene and water, separate the layers, cool the organic layer to -5-0°C, stir, and filter to obtain 65.2g of 2-chloro-3-phenylpropionamide with a yield of 66%. 1H NMR (500MHz, DMSO): δ7.65 (s, 1H), 7.30 (t, J = 7.3Hz, 3H), 7.27–7.19 (m, 3H), 4. 52(t,J=7.4Hz,1H), 3.27(dd,J=13.9,7.0Hz,1H), 3.01(dd,J=13.9,7.8Hz,1H).

[0107] Example 6: Synthesis of methyl 2-chloro-3-(3-trifluoromethylphenyl)propionate

[0108] 2-Chloro-3-(3-trifluoromethylphenyl)propionitrile (140 g) and methanol were added to the reaction flask in sequence, hydrogen chloride (40 g) was introduced, and the temperature was raised to reflux. After the reaction was complete, methanol was removed under reduced pressure, extracted, and concentrated to obtain 151 g of methyl 2-chloro-3-(3-trifluoromethylphenyl)propionate, with a yield of 97%.

[0109] Example 7: Synthesis of methyl 2-chloro-3-(3-trifluoromethylphenyl)propionate

[0110] 2-Chloro-3-(3-trifluoromethylphenyl)propionic acid (120 g), methanol and concentrated sulfuric acid (15 g) were added to the reaction flask in sequence, and the temperature was raised to reflux. After the reaction was complete, extraction was performed, and the organic phase was concentrated to obtain 124.7 g of methyl 2-chloro-3-(3-trifluoromethylphenyl)propanoate, with a yield of 98%.

[0111] Example 8: Synthesis of ethyl 2-chloro-3-phenylpropionate

[0112] Anhydrous ethanol, 2-chloro-3-phenylpropionic acid (90%, 143g), and concentrated sulfuric acid (10g) were added to the reaction flask in sequence, and the temperature was raised to reflux for reaction. After the reaction was complete, extraction was performed, and the organic phase was concentrated to obtain 153g of ethyl 2-chloro-3-phenylpropionate with a yield of 95%. 1 HNMR (500MHz, DMSO): δ7.30(ddd,J=7.4,4.5,1.4Hz,2H),7.27–7.17(m,3H),4.43(t,J=7.5Hz,1H),4.17( qd,J=7.1,2.9Hz,2H), 3.35(dd,J=14.0,7.3Hz,1H), 3.17(dd,J=14.0,7.6Hz,1H), 1.21(t,J=7.1Hz,3H).

[0113] Example 9: Synthesis of 2-chloro-3-phenylpropionic acid

[0114] 30% hydrochloric acid (60g) and 2-chloro-3-phenylpropionamide (94%, 65.2g) were added to the reaction bottle in sequence, and the temperature was raised to reflux for reaction. After the reaction was complete, the temperature was lowered, suction filtered, and dried to obtain 51.5g of 2-chloro-3-phenylpropionic acid with a yield of 82%.

[0115] Example 10: Synthesis of 3-phenyl-2-(3-trifluoromethylbenzyl)oxirane-2-carboxylic acid

[0116] 2-Chloro-3-(3-trifluoromethylphenyl)propionic acid methyl ester (151g), benzaldehyde (67.4g), and DMF were added to the reaction bottle in sequence, cooled to -5-0°C, and sodium methoxide (37.2g) was added in batches. After the reaction was complete, 30% sodium hydroxide aqueous solution (85g) was added dropwise, and the temperature was raised to 20-30°C. After the reaction was complete, acidification, extraction, and concentration were performed to obtain 170g of 3-phenyl-2-(3-trifluoromethylbenzyl)oxirane-2-carboxylic acid, with a yield of 96%. 1 H NMR(500MHz,DMSO-)δ:13.40(s,1H),7.85–6.74(m,9H),4.50(s,1H),3.30(s,1H),3.27(s,1H).

[0117] Example 11: Synthesis of ethyl 3-(3-trifluoromethylphenyl)-2-benzyloxirane-2-carboxylate

[0118] Ethyl 2-chloro-3-phenylpropionate (92%, 153g), m-trifluoromethylbenzaldehyde (115g), and DMF were added to the reaction bottle in sequence, cooled to -5-0°C, and sodium methoxide (46.5g) was added in batches. After the reaction was complete, toluene and water were added, and 30% concentrated hydrochloric acid (113g) was added dropwise. The layers were separated, and the organic phase was concentrated to obtain 212g of ethyl 3-(3-trifluoromethylphenyl)-2-benzyloxirane-2-carboxylate, with a yield of 88%. 1 H NMR (500MHz, DMSO): δ7.78(dd,J=19.4,11.0Hz,2H),7.74–7.56(m,2H),7.42–7.25(m,3H),7.21(dd,J=19.4,7.2Hz,2 H), 4.63 (s, 1H), 4.14 (dd, J = 18.0, 7.1Hz, 2H), 3.22 (d, J = 15.1Hz, 1H), 2.37 (d, J = 15.1Hz, 1H), 1.15 (t, J = 7.1Hz, 3H).

[0119] Example 12: Synthesis of ethyl 3-(3-pyridine)-2-(3-trifluoromethylbenzyl)oxirane-2-carboxylate

[0120] Ethyl 2-chloro-3-phenylpropionate (28.1 g), 3-pyridinecarboxaldehyde (10.7 g), and DMF were added to the reaction bottle in sequence, cooled to -5-0°C, and sodium ethoxide (8.8 g) was added in batches. After the reaction was complete, toluene and water were added, and 30% hydrochloric acid (17 g) was added dropwise. The layers were separated, and the organic phase was concentrated to obtain 33.5 g of ethyl 3-(3-pyridine)-2-(3-trifluoromethylbenzyl)oxirane-2-carboxylate, with a yield of 83%. 1 H NMR (500MHz, DMSO): δ7.48(dd,J=7.8,4.8Hz,1H),7.42–7.25(m,5H),7.22(dd,J=10.5,7.6Hz,2H),4.4 4(s,1H),3.81(q,J=7.1Hz,2H),3.65(d,J=14.7Hz,1H),2.98(d,J=14.7Hz,1H),0.77(t,J=7.1Hz,3H).

[0121] Example 13: Synthesis of 3-(3-trifluoromethylphenyl)-2-benzyloxirane-2-carboxylic acid

[0122] The crude product of ethyl 3-(3-trifluoromethylphenyl)-2-benzyloxirane-2-carboxylate (93%, 212 g) and ethanol were added to a reaction bottle, 30% sodium hydroxide solution (93.3 g) was added dropwise, and the temperature was raised to 20-30° C. for reaction. After the reaction was complete, the mixture was concentrated, toluene and water were added, 30% hydrochloric acid (92.2 g) was added dropwise, the layers were separated, and the organic phase was concentrated to obtain 192 g of 3-(3-trifluoromethylphenyl)-2-benzyloxirane-2-carboxylic acid, with a yield of 96%. 1 H NMR (500MHz, DMSO): δ13.04(s,1H),7.74–7.64(m,3H),7.60(t,J=7.6Hz,1H),7.37–7.30 (m,4H),7.29–7.24(m,1H),4.42(s,1H),3.66(d,J=14.7Hz,1H),2.93(d,J=14.7Hz,1H).

[0123] Example 14: Synthesis of 3-(3-pyridine)-2-(3-trifluoromethylbenzyl)oxirane-2-carboxylic acid

[0124] 3-(3-pyridine)-2-(3-trifluoromethylbenzyl)oxirane-2-carboxylic acid ethyl ester (33.5 g) and ethanol were added to a reaction bottle, 30% sodium hydroxide solution (13.3 g) was added dropwise, and the temperature was raised to 20-30° C. for reaction. After the reaction was complete, the mixture was concentrated, toluene and water were added, 30% hydrochloric acid (13.1 g) was added dropwise, the layers were separated, and the organic phase was concentrated to obtain 27.4 g of 3-(3-pyridine)-2-(3-trifluoromethylbenzyl)oxirane-2-carboxylic acid, with a yield of 91%. 1 H NMR (500MHz, DMSO): δ8.62(s,1H),7.84(d,J=7.8Hz,1H),7.36–7.25(m,4H),7 .25–7.17(m,3H),4.54(s,1H),3.23(d,J=15.0Hz,1H),2.37(d,J=15.0Hz,1H).

[0125] Example 15: Synthesis of 3-(3-trifluoromethylphenyl)-2-benzyloxirane-2-carboxylic acid dicyclohexylamine salt

[0126] The crude product of 3-(3-trifluoromethylphenyl)-2-benzyloxirane-2-carboxylic acid (94%, 200 g) was added to n-hexane, stirred, and dicyclohexylamine (158.8 g) was added dropwise. The mixture was stirred at room temperature for 1 hour to precipitate a solid. The solid was filtered off with suction, and the filter cake was rinsed with n-hexane and dried to obtain 288 g of 3-(3-trifluoromethylphenyl)-2-benzyloxirane-2-carboxylic acid dicyclohexylamine salt. The yield was 95%.

[0127] Example 16: Synthesis of 3-(3-trifluoromethylphenyl)-2-benzyloxirane-2-carboxylic acid calcium salt

[0128] Add crude 3-(3-trifluoromethylphenyl)-2-benzyloxirane-2-carboxylic acid (94%, 200g) to water, stir, and drop 30% sodium hydroxide solution (93.4g). After stirring at room temperature until dissolved, add calcium chloride (97.2g), stir for 2h, and solid precipitate. Filter by suction, rinse the filter cake with 100g of water, and dry to obtain 197.6g of 3-(3-trifluoromethylphenyl)-2-benzyloxirane-2-carboxylic acid calcium salt, with a yield of 92%.

[0129] Example 17: Synthesis of 3-phenyl-2-(3-trifluoromethylbenzyl)oxirane-2-carboxylic acid sodium salt

[0130] Add crude 3-phenyl-2-(3-trifluoromethylbenzyl)oxirane-2-carboxylic acid (94%, 200 g) to water, add 30% sodium hydroxide solution (93.4 g) dropwise, stir at room temperature until dissolved, add chloroform, stir, separate into layers, and obtain 415 g of chloroform solution in the lower layer, which is directly used for the next step of reaction.

[0131] Example 18: Synthesis of 1-phenyl-3-(3-trifluoromethylphenyl)-2-propanone

[0132] Add DMAC and aluminum chloride (14.7 g) to the reaction bottle, heat to reflux, and add 3-(3-trifluoromethylphenyl)-2-benzyloxirane-2-carboxylic acid dicyclohexylamine salt (97%, 288 g) in batches. After the addition is complete, keep warm for reaction. After the reaction is complete, concentrate to remove the solvent, extract, dry, and concentrate to obtain 135.6 g of 1-phenyl-3-(3-trifluoromethylphenyl)-2-propanone, with a yield of 86%.

[0133] Example 19: Synthesis of 1-phenyl-3-(3-trifluoromethylphenyl)-2-propanone

[0134] Add DMF and magnesium chloride (10.2 g) to the reaction flask, raise the temperature to reflux, and add 3-(3-trifluoromethylphenyl)-2-benzyloxirane-2-carboxylic acid calcium salt (93%, 197.6 g) in batches. After the addition is complete, keep the temperature to react. After the reaction is complete, concentrate to remove the solvent, extract, dry, and concentrate to obtain 129.3 g of 1-phenyl-3-(3-trifluoromethylphenyl)-2-propanone, with a yield of 84%.

[0135] Example 20: Synthesis of 1-phenyl-3-(3-trifluoromethylphenyl)-2-propanone

[0136] Toluene and ferric chloride (17.9 g) were added to the reaction flask, the temperature was raised to reflux, and the chloroform solution of 3-phenyl-2-(3-trifluoromethylbenzyl)oxirane-2-carboxylic acid sodium salt prepared in Example 17 was added dropwise. After the addition was complete, the mixture was refluxed for reaction. After the reaction was complete, the solvent was removed by concentration, extraction was performed, drying was performed, and concentration was performed to obtain 126.7 g of 1-phenyl-3-(3-trifluoromethylphenyl)-2-propanone, and the total yield of the two steps was 71%.

[0137] Example 21: Synthesis of 1-phenyl-3-(3-trifluoromethylphenyl)-2-propanone

[0138] Add DMF and aluminum chloride (6.65 g) to the reaction flask, heat to reflux, and dropwise add a DMF solution of 3-phenyl-2-(3-trifluoromethylbenzyl)oxirane-2-carboxylic acid (170 g). After the dropwise addition is complete, reflux for reaction. After the reaction is complete, extract, dry, and concentrate to obtain 142 g of 1-phenyl-3-(3-trifluoromethylphenyl)-2-propanone with a yield of 98%. 1 H NMR (500MHz, DMSO): δ7.67–7.40(m,4H),7.37–7.09(m,5H),3.89(s,2H),4.01(s,2H).

[0139] Example 22: Synthesis of 1-phenyl-3-(3-trifluoromethylphenyl)-2-propanone

[0140] Add DMF and ferric chloride (9.1 g) to the reaction flask, heat to reflux, and dropwise add a DMF solution of 3-(3-trifluoromethylphenyl)-2-benzyloxirane-2-carboxylic acid (94%, 192 g). After the dropwise addition is complete, heat and react. After the reaction is complete, extract, dry, and concentrate to obtain 155 g of 1-phenyl-3-(3-trifluoromethylphenyl)-2-propanone, with a yield of 98%.

[0141] Example 23: Synthesis of 1-(3-trifluoromethylphenyl)-3-(3-pyridine)-2-acetone

[0142] Add DMF and magnesium chloride (1.4 g) to the reaction flask and heat to reflux. Add dropwise a DMF solution of 3-(3-pyridine)-2-(3-trifluoromethylbenzyl)oxirane-2-carboxylic acid (89%, 27.4 g). After the addition is complete, heat the mixture to react. After the reaction is complete, extract, dry, and concentrate to obtain 21.4 g of 1-(3-trifluoromethylphenyl)-3-(3-pyridine)-2-propanone with a yield of 98%. 1 H NMR (500MHz, DMSO): δ7.57 (d, J = 7.8 Hz, 1H), 7.33 (dd, J = 13.4, 6.3 Hz, 3H), 7.28–7.15 (m, 4H), 3.93 (s, 2H), 3.90 (s, 2H).

Claims

1. A method for preparing a 1-aryl-3-substituted acetone compound 1, characterized in that: The epoxycarboxylic acid compound 2 or its salt 3 is decarboxylated and rearranged under the action of the catalyst 1 to obtain 1-aryl-3-substituted acetone 1, which is represented by the following equation: or in, R 1 is any one of phenyl, substituted phenyl, unsubstituted or substituted pyridyl; the substitution is any one or more of halogen-substituted C1-C10 alkyl, and the halogen is any one or more of F, Cl, Br, I; Ar is phenyl, Any one of heteroaryl groups containing 1 to 4 atoms selected from nitrogen, oxygen and sulfur atoms; n is an integer from 1 to 5. When n is an integer not less than 2, multiple R 2 Can be the same or different; R 2 is one or more of halogen, cyano, nitro, unsubstituted or halogen-substituted alkyl, and amino; halogen is F, Cl, Br, and I; M is an ammonium ion, an alkali metal ion, or an alkaline earth metal ion; the alkali metal is sodium or potassium, and the alkaline earth metal is calcium; When M is an ammonium ion or an alkali metal ion, m is 1; When M is an alkaline earth metal ion, m is 2; The ammonium ion is Catalyst 1 is a proton acid or a Lewis acid; the proton acid is hydrofluoric acid, sulfuric acid, or phosphoric acid; the Lewis acid is AlCl3, FeCl3, SbCl5, SnCl4, BCl3, TiCl4, or ZnCl 2、 MgCl2.

2. The method according to claim 1, characterized in that: The R 1 is any one of phenyl, 3-trifluoromethylphenyl, and pyridyl; Ar is phenyl, n is 1; R 2 It is a C1~C10 alkyl group substituted with halogen.

3. The method according to claim 2, characterized in that The Ar is phenyl or 3-trifluoromethylphenyl.

4. A method for preparing an epoxycarboxylic acid compound 2 or a salt thereof 3, characterized in that: Step 1: Aromatic amine 4 reacts with a diazotizing agent to generate a diazonium salt, which then reacts with olefin 5 in the presence of a catalyst 2 to obtain an intermediate 6; Step 2: Intermediate 6 reacts with alcohol 7 to prepare intermediate 8; Step 3: Intermediate 8 reacts with aldehyde 9 under the action of base 1 to obtain intermediate 10; The fourth step: the intermediate 10 is hydrolyzed under the action of base 2 to obtain epoxycarboxylic acid compound 2; or the fifth step is also included: the epoxycarboxylic acid compound 2 is reacted with base 3 to obtain epoxycarboxylate 3; the formula is as follows: Among them, Ar, R 1 , M, m are defined as in claim 1; R 3 For cyano, COR 4 ; R 4 is hydroxyl, C1-C10 alkoxy, amino; R 5 is a C1-C10 alkyl group; X is a halogen; The diazotizing agent is an alkali metal nitrite; Base 1 is an alkali metal or alkaline earth metal hydroxide, an alkali metal or alkaline earth metal carbonate, an alkali metal or alkaline earth metal alcoholate, an alkali metal or alkaline earth metal hydride, and a mixture thereof; Base 2 is an alkali metal or alkaline earth metal hydroxide, or an alkali metal or alkaline earth metal carbonate; Base 3 is an organic base or an inorganic base; the organic base is triethylamine, cyclohexanediamine, pyridine, tetrahydropyrrole, hexahydropyridine, morpholine, triethylenediammonium (DABCO), or diazabicyclo (DBU); the inorganic base is ammonia gas, ammonia water, an alkali metal or alkaline earth metal hydroxide, or an alkali metal or alkaline earth metal carbonate; The alkali metal is sodium or potassium, and the alkaline earth metal is calcium; Catalyst 2 is a metal halide, and the metal is copper.

5. The method according to claim 4, characterized in that The base 1 is sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide; the base 2 is sodium hydroxide or potassium hydroxide.

6. The method according to claim 4, characterized in that Epoxycarboxylic acid compound 2 is prepared from intermediate 8 in one pot, as shown in the following equation: Among them, Ar, R 1 , R 5 , X, base 1, base 2 are defined as described in claim 4.

7. An epoxycarboxylic acid compound 2 or a salt thereof 3, characterized in that: The structural formula of the epoxy carboxylic acid compound 2 is: The structural formula of epoxy carboxylic acid compound salt 3 is: in, The R 1 is phenyl, substituted phenyl, unsubstituted or substituted pyridyl; the substitution is any one or more of C1-C10 alkyl substituted with halogen, and the halogen is any one or more of F, Cl, Br, and I; Ar is phenyl, Contains 1-4 any one of the heteroaryl groups selected from nitrogen, oxygen, and sulfur atoms; n is an integer of 1-5, when n is an integer not less than 2, multiple R 2 Can be the same or different; R 2 is one or more of halogen, cyano, nitro, unsubstituted or halogen-substituted alkyl, and amino; halogen is F, Cl, Br, and I; M is an ammonium ion, an alkali metal ion, or an alkaline earth metal ion; When M is an ammonium ion or an alkali metal ion, m is 1; When M is an alkaline earth metal ion, m is 2.

8. The compound according to claim 7, characterized in that The R 1 is any one of phenyl, 3-trifluoromethylphenyl, and pyridyl; Ar is phenyl, n is 1; R 2 is a halogen-substituted C1-C10 alkyl group; The ammonium ion is R 6 -R 9 They are independently H, C1-C10 alkyl, C3-C10 cycloalkyl, heterocycloalkyl containing nitrogen, oxygen and sulfur atoms, and C6-C12 aryl; Y can be any one of C, N, O and S; and p is any integer from 0 to 2.

9. The compound according to claim 7, characterized in that The ammonium ion is 10. The compound according to claim 8, characterized in that The ammonium ion is

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