A preparation method of 1,3-disubstituted-2-acetone compounds and intermediates thereof

Abstract

This invention relates to a method for preparing 1,3-disubstituted 2-propanone compounds and its intermediates. The method includes: reacting compound II and compound III with a diazotizing agent in the presence of catalyst 1 to obtain compound IV; and reacting compound IV under certain conditions to obtain compound I. This invention has the following advantages: inexpensive and readily available raw materials, mild reaction conditions, environmental friendliness, and high safety. The reaction formula of this invention is as follows:

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and specifically relates to a preparation method of 1,3-disubstituted-2-acetone compounds and intermediates thereof. Background Art

[0002] 1,3-disubstituted-2-acetone compounds are a class of compounds with biological activity. Patent CN110478338A reports that butyrolactone metabolite ketone (Compound A) has the effect of lowering blood lipids.

[0003]

[0004] 1,3-disubstituted-2-acetone compounds are also an important class of organic synthesis intermediates. In the field of medicine, 1,3-disubstituted-2-acetone compounds can be used as intermediates to prepare hypoglycemic drugs (CN110041182A), choleretic drugs such as choleretics, anti-epileptic drugs such as methyltoin (CN107118086A), such as o-(p-)hydroxyphenylacetone can be used to synthesize 3-bromo-4-hydroxyphenylacetone, antiasthmatic drugs such as fenoterol and a variety of new adrenergic receptor antagonist drugs (CN101544552B); 4-hydroxy-3-methoxyphenylacetone can be used to synthesize carbidopa, a drug for the treatment of Parkinson's syndrome (CN107986949A).

[0005] In the field of pesticides, 1,3-disubstituted-2-acetone compounds can be used to prepare pesticides such as sodium diphacinone (CN1091090C).

[0006] In addition, it is used in the synthesis of photoelectric crystalline conductor materials in microporous materials, crystalline photoconductors, synthetic graphene fragments, etc. (CN107118086A, CN109942389, CN110041182A).

[0007] At present, the main synthesis methods of 1,3-disubstituted-2-acetone compounds are as follows:

[0008] The first method for preparing 1,3-disubstituted-2-acetone compounds is to use two molecules of phenylacetic acid (R is H) or ester (R is alkyl) compounds as raw materials to prepare 1,3-disubstituted acetone compounds through a series of reactions.

[0009] Using phenylacetic acid as the starting material, DCC as a dehydrating agent, and DMAP as a catalyst, a condensation reaction is performed to prepare 1,3-disubstituted-2-acetone compounds (CN109942389A, CN110041182A). The reaction formula 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 using this method to prepare asymmetric products, cross-condensation side reactions will occur, and the products need to be separated by column chromatography, which is not suitable for industrial production.

[0012] Using methyl phenylacetate as raw material, 1,3-diphenylacetone (CN1680246A) is prepared by gas phase catalytic hydrogenation in the presence of a composite manganese-aluminum catalyst. The reaction formula is as follows:

[0013]

[0014] This method requires the use of expensive metal catalysts, and the reaction selectivity of 1,3-phenylacetone is 23-67%, the reaction yield is low, the post-processing operation is cumbersome, and it is only suitable for the preparation of symmetrical 1,3-disubstituted-2-acetone compounds.

[0015] The second method for preparing 1,3-disubstituted-2-acetone compounds is to react halogen-substituted aromatic chlorides with p-toluenesulfonylmethyl isocyanide to prepare 1,3-disubstituted halogen phenyl-2-acetone (CN110002975A), with a yield of 60%. The reaction formula is as follows:

[0016]

[0017] This method requires the use of isocyanide, the reaction has a foul odor and toxicity, and the product needs to be separated and purified by column chromatography, which makes post-processing difficult. In addition, this method is only suitable for preparing structurally symmetrical 1,3-disubstituted-2-acetone compounds.

[0018] The third method for preparing 1,3-disubstituted-2-acetone compounds is to use benzyl halide as raw material, and react Grignard reagent with ester to obtain 1,3-disubstituted-2-acetone (CN109796317A), and the reaction formula is as follows:

[0019]

[0020] In this method, anhydrous lithium chloride is added to form a stable and less active benzyl magnesium lithium chloride when preparing the Grignard reagent to avoid the self-condensation side reaction of the benzyl halide. Although this method can be effectively used to prepare structurally asymmetric 1,3-disubstituted-2-propanone compounds, the Grignard reaction conditions are harsh (anhydrous and oxygen-free), and the 1,3-disubstituted-2-ketopropanone compounds will further add to obtain tertiary alcohol byproducts (Journal of the Indian Chemical Society, 2008, 85(3), 300-305,); and the reaction raw materials are expensive and the cost is high.

[0021] The fourth method for preparing 1,3-disubstituted-2-acetone compounds is to use substituted benzaldehyde as a raw material and acetophenone to obtain the target product through five steps of condensation, oxidation, chlorination, reduction, and reoxidation (US4212998A). The yield of the five-step reaction is 39.5%. The reaction formula is as follows:

[0022]

[0023] This method has a long reaction route and uses tin tetrachloride epoxy ring opening, which will produce a large amount of difficult-to-treat metal-containing waste liquid, making post-treatment difficult; the benzyl hydrogenation reduction catalyst is Pd / C, which is expensive; the oxidation process uses hydrogen peroxide, which poses a safety hazard; and the oxidant used in this route is pyridinium chlorochromate (PCC), which is toxic and poses a great threat to humans and the environment.

[0024] The fifth method for preparing 1,3-disubstituted-2-acetone compounds is to use m-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 m-trifluoromethylbenzyl cyanide as a raw material, which better solves the side reaction of Claisen ester self-condensation. However, benzyl cyanide compounds, especially substituted benzyl cyanide raw materials, are difficult to prepare and expensive. For example, the preparation method of m-trifluoromethylbenzyl cyanide is to obtain m-trifluoromethylbenzene 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.

[0027] In view of this, the present invention is proposed. Summary of the invention

[0028] In view of the deficiencies in the prior art, the present invention provides a method for preparing 1,3-disubstituted-2-acetone compounds and intermediates thereof, which have the advantages of cheap and readily available raw materials, mild reaction conditions, green environmental protection and high safety.

[0029] The first object of the present invention is to provide a method for preparing a 1,3-disubstituted propan-2-one compound I, the method comprising:

[0030] Compound II reacts with compound III in the presence of a diazotizing agent and catalyst 1 to obtain compound IV.

[0031] Compound IV reacts to generate compound I under certain conditions.

[0032]

[0033] Wherein, Ar is any one of an unsubstituted or substituted C6-C12 aryl group, an unsubstituted or substituted heteroaryl group containing 1-4 atoms selected from nitrogen, oxygen, and sulfur atoms;

[0034] Preferably, Ar is phenyl or Any of the following;

[0035] When Ar is When n is an integer of 1-5, such as 1, 2, 3, 4, 5; when n is an integer not less than 2, multiple R 1 Can be the same or different;

[0036] R 1 is one or more selected from halogen, cyano, nitro, unsubstituted or substituted alkyl, and unsubstituted or substituted amino; preferably one or more selected from nitro, and unsubstituted or substituted C1-C10 alkyl;

[0037] More preferably, n is 1; R 1 Any one or more of nitro or halogen-substituted C1-C10 alkyl, halogen being F, Cl, Br, I;

[0038] When Ar is an unsubstituted or substituted heteroaryl group, it is preferably an unsubstituted or substituted five-membered or six-membered heteroaryl group, especially an unsubstituted or substituted pyridyl group.

[0039] X is any one of halogen, nitrate, sulfate or sulfite,

[0040] When X is a halogen, X is any one of F, Cl, Br and I.

[0041] R is any one of hydrogen, unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C6-C12 aryl, and unsubstituted or substituted heteroaryl containing 1-4 atoms selected from nitrogen, oxygen, and sulfur atoms;

[0042] When R is an unsubstituted C6-C12 aryl group, it is preferably a phenyl group;

[0043] When R is a substituted C6-C12 aryl group, it is preferably a substituted phenyl group, such as any one or more of a nitro group and a halogen-substituted C1-C10 alkyl group, and the halogen group is any one or more of F, Cl, Br, and I;

[0044] When R is an unsubstituted or substituted heteroaryl group containing 1-4 atoms selected from nitrogen, oxygen and sulfur atoms, the number of heteroatoms is 1, 2, 3 or 4, preferably 1 or 2, and more preferably an unsubstituted or substituted pyridyl group.

[0045] The EWG is -CN or -COR 2 Any one of the following; where R 2 is unsubstituted or substituted amino or -OR 3 , the R 3 Any one of hydrogen, unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C6-C12 aryl, and unsubstituted or substituted heteroaryl containing 1-4 atoms selected from nitrogen, oxygen, and sulfur atoms;

[0046] Preferably,

[0047] R 2 When it is a substituted amino group, it is a mono- or di-substituted amino group,

[0048] R 3 Any one of unsubstituted or substituted C1-C8 alkyl, unsubstituted or substituted C6-C8 aryl, and unsubstituted or substituted heteroaryl containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur atoms;

[0049] More preferred EWG is -CN, -CONH2, -COOR 3 , the R 3 is hydrogen, unsubstituted or substituted C1-C10 alkyl, typically R 3 It is any one of hydrogen, methyl and ethyl.

[0050] The above substituents are common substituents in the chemical field, such as halogen, hydroxyl, CN, COOH, CONH2, NO2, NH2, CF3, etc. The above alkyl groups include straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl groups, and heterocycloalkyl groups.

[0051] The diazotization reagent includes any one or more of alkali metal nitrites, nitrite esters, nitrosyl sulfuric acid, and nitrous acid gas. Preferably, the diazotization reagent is an alkali metal nitrite, and more preferably, the alkali metal nitrite is sodium nitrite.

[0052] The catalyst 1 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.

[0053] The molar ratio of compound II to compound III is 1-5:1, preferably 1-5:1, and more preferably 1-2:1.

[0054] The molar ratio of the diazotizing agent to compound III is 0.5-2:1, preferably 1-2:1, and more preferably 1-1.5:1.

[0055] The molar ratio of the compound III to the catalyst 1 is 1-100:1, preferably 5-100:1, and more preferably 5-50:1.

[0056] The reaction of compound II to compound III is carried out in a solvent, and the solvent is water, a polar or non-polar solvent or a mixture thereof.

[0057] Polar solvents such as alcohols, ketones, furans, such as methanol, ethanol, DMF, acetone, tetrahydrofuran, etc.

[0058] Non-polar solvents such as benzene, chloroform, ether, carbon tetrahalide, etc.

[0059] Preferably it is a polar solvent, more preferably a ketone solvent, specifically acetone.

[0060] When compound II reacts with compound III, a protonic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, etc., is added to the reaction.

[0061] Preferably, compound IV can be used to prepare compound I in the presence of base 1 or under the catalysis of acid or base 2;

[0062] Among them, base 1 is an organic base or an inorganic base or a combination thereof, preferably any one or more of alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal alcoholates, alkaline earth metal alcoholates, alkali metal carbonates, and alkaline earth metal carbonates, preferably alkali metal hydroxides, such as any one or more of potassium hydroxide and sodium hydroxide, more preferably sodium hydroxide.

[0063] The acid is a Lewis acid, such as AlCl3, FeCl3, SbCl5, SnCl4, BF3, BCl3, TiCl4, ZnCl2, MgCl2; or a protonic acid, such as hydrofluoric acid, sulfuric acid, phosphoric acid, etc.; or any one or more of alkyl aluminums,

[0064] Preferred Lewis acids are any one or more of AlCl3, FeCl3, SnCl4, TiCl4, ZnCl2, and MgCl2.

[0065] Base 2 can be an organic base or an inorganic base or a combination thereof, such as any one or more of alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, and alkaline earth metal carbonates, specifically any one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate.

[0066] The reaction of compound IV to prepare compound I can be carried out in the presence or absence of a solvent, wherein the solvent is water, a polar or non-polar solvent or a mixture thereof, preferably any one or more of ketones, alcohols and nitrile solvents;

[0067] Ketone solvents, preferably C3-C9 ketone solvents, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, methyl hexyl ketone, diacetone alcohol, etc.

[0068] The alcohol solvent is preferably a C1-C10 alcohol solvent, such as methanol, ethanol, propanol, isopropanol, butanol, octanol, ethylene glycol, propylene glycol, glycerol, etc.

[0069] The nitrile solvent is preferably a C2-C8 nitrile solvent, such as acetonitrile, propionitrile, butyronitrile and the like.

[0070] The second object of the present invention is to provide a new intermediate IV.

[0071]

[0072] R, Ar, X, and EWG are as defined above.

[0073] When R is a substituted alkyl group, R is not a substituted cyclopropyl group, an unsubstituted or substituted ethyl difluoroacetate alkyl group, or an unsubstituted or substituted difluoroamido alkyl group.

[0074] Preferably Ar is phenyl or or an unsubstituted or substituted heteroaryl group containing 1 to 4 atoms selected from nitrogen, oxygen and sulfur atoms,

[0075] When Ar is When n is 1, R 1 is nitro or trifluoromethyl;

[0076] When Ar is heteroaryl, Ar is pyridyl;

[0077] R is any one of hydrogen, phenyl, nitrophenyl, trifluoromethylphenyl or pyridyl;

[0078] X is Cl.

[0079] The third object of the present invention is to provide a method for preparing compound II:

[0080] The compound II is prepared by coupling reaction of compound V with compound VI under the action of catalyst 2, and the reaction equation is as follows:

[0081]

[0082] R and EWG are defined as above.

[0083] The catalyst 2 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 or more of DABCO, DMAP or DBU.

[0084] The molar ratio of compound VI to compound V is 1:0.3-5, preferably 1:0.5-2, and more preferably 1:0.8-1.5.

[0085] The molar ratio of the compound V to the catalyst 2 is 1-15:1, preferably 1-10:1, and more preferably 1-6:1.

[0086] Compared with the prior art, the present invention has significant technical effects:

[0087] 1. The raw and auxiliary materials are all basic raw materials, cheap and easy to obtain, without odor or toxicity, and the carbon skeleton construction strategy is new. Because the route cost is low and meets occupational health requirements, it is suitable for industrial production;

[0088] 2. Mild reaction conditions, high safety; simple post-treatment and easy operation;

[0089] 3. The reaction to prepare 2-ketone compounds has a wide range of applications. The raw materials will not undergo self-condensation or side reactions such as tertiary alcohol compounds generated by Grignard reaction. It is especially suitable for the preparation of 1,3-asymmetric disubstituted-2-acetone compounds;

[0090] 4. Avoid the generation of large amounts of three wastes, such as 1,3-dicyclohexylurea, metal-containing waste liquid, etc. The reaction route is green and environmentally friendly;

[0091] 5. The reaction has good atom economy and high yield. DETAILED DESCRIPTION

[0092] 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.

[0093] Example 1: Preparation of 2-chloro-3-hydroxy-3-phenyl-2-(3-(trifluoromethyl)benzyl)propionitrile

[0094] 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 reactor and stir to mix evenly. Control the temperature of the reaction liquid to 0-5°C, drop 91.2 g of 30% hydrochloric acid aqueous solution, then drop 67 g of sodium nitrite solution (40% aqueous solution), and stir until the reaction is completed. The organic layer is desolventized and purified to obtain the target product 75 g of 2-chloro-3-hydroxy-3-phenyl-2-(3-(trifluoromethyl)benzyl)propionitrile, with a yield of 74%.

[0095] 1H NMR (500Hz, CDCl3) 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.

[0096] Example 2: Preparation of 2-chloro-3-hydroxy-3-phenyl-2-(3-(trifluoromethyl)benzyl)propionic acid

[0097] 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 reactor and stir to mix evenly. Control the temperature of the reaction solution to 10-20°C, drop 30.4 g of 30% hydrochloric acid aqueous solution, then drop 19 g of sodium nitrite aqueous solution, and stir until the reaction is completed. The organic layer is desolventized and purified to obtain 25 g of the target product 2-chloro-3-hydroxy-3-phenyl-2-(3-(trifluoromethyl)benzyl)propionic acid, with a yield of 70%.

[0098]

[0099] 1 H NMR (500Hz, CDCl3) δ7.37-7.53(m,9H),5.28(s,1H),3.55(d,J=13.9Hz,1H),2.89(d,J=13.9Hz,1H).ESI-MS m / z:[MH] - =357.09

[0100] Example 3: Preparation of 2-chloro-3-hydroxy-3-phenyl-2-(3-(trifluoromethyl)benzyl)propionic acid

[0101] 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 reactor and stir to mix evenly. Control the temperature of the reaction liquid to 10-20°C, drop 18.3g of 30% hydrochloric acid aqueous solution, then drop 19g of sodium nitrite aqueous solution (40% aqueous solution), and stir until the reaction is completed. The organic layer is desolventized and purified to obtain 14.6g of the target product 2-chloro-3-hydroxy-3-phenyl-2-(3-(trifluoromethyl)benzyl)propionic acid, with a yield of 68%.

[0102] Example 4: Preparation of methyl 2-chloro-3-hydroxy-3-phenyl-2-(3-(trifluoromethyl)benzyl)propionate

[0103] Add 38.4g of methyl 2-(hydroxy(phenyl)ethyl)acrylate, 90g of acetone, 32.2g of m-trifluoromethylaniline, and 1g of cuprous chloride to the reactor and stir to mix evenly. Control the temperature of the reaction solution to 10°C, add 60g of 30% hydrochloric acid aqueous solution, and drip for 0.5h. Continue to keep warm and add 38g of sodium nitrite aqueous solution (40% aqueous solution) and stir until the reaction is completed. The organic layer is purified by solvent removal to obtain the target product 51g of methyl 2-chloro-3-hydroxy-3-phenyl-2-(3-(trifluoromethyl)benzyl)propionate, with a yield of 68%.

[0104]

[0105] 1 H NMR (500Hz, CDCl3) 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:[MH] - =372.15.

[0106] Example 5: Preparation of ethyl 2-chloro-3-hydroxy-3-phenyl-2-(3-(trifluoromethyl)benzyl)propionate

[0107] 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 reactor and stir to mix evenly. Control the temperature of the reaction liquid to 10°C, drop 30g of 30% hydrochloric acid aqueous solution, then drop 17.3g of sodium nitrite aqueous solution (40% aqueous solution), and stir until the reaction is completed. The organic layer is desolventized and purified to obtain the target product 27g of ethyl 2-chloro-3-hydroxy-3-phenyl-2-(3-(trifluoromethyl)benzyl)propionate, with a yield of 70%.

[0108]

[0109] 1 H NMR (500Hz, CDCl3) δ7.43-7.18(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:[MH] - =386.14.

[0110] Example 6: Preparation of 2-chloro-3-hydroxy-3-phenyl-2-(3-(nitro)benzyl)propionic acid

[0111] Add 7.12g of 2-(hydroxy(phenyl)methyl)acrylic acid, 18g of acetone, 6.9g of m-nitroaniline, and 0.1g of cuprous chloride to the reactor and stir to mix evenly. Control the temperature of the reaction liquid to 10-20°C, drop 15.2g of 30% hydrochloric acid aqueous solution, then drop 9.5g of sodium nitrite aqueous solution (40% aqueous solution), and stir until the reaction is completed. The organic layer is purified to obtain the target product 2-chloro-3-hydroxy-3-phenyl-2-(3-(nitro)benzyl)propionic acid 12.4g, with a yield of 74%.

[0112]

[0113] 1 H NMR(500Hz,DMSO-d6)δ7.24–8.16(m,9H),5.00(s,1H),3.70(d,J=13.9Hz,1H),2.86(d,J=14.0Hz,1H).ESI-MS m / z:[MH] - =334.18.ESI-MS m / z:[MH] - =334.18.

[0114] Example 7: Preparation of 2-chloro-3-hydroxy-3-phenyl-2-(3-(nitro)benzyl)ethyl acrylate

[0115] Add 7.88g of ethyl 2-(hydroxy(phenyl)methyl)acrylate, 18g of acetone, 6.9g of m-nitroaniline, and 0.1g of cuprous chloride to the reactor and stir to mix evenly. Control the temperature of the reaction liquid to 10°C, add 15.2g of 30% hydrochloric acid aqueous solution, and add it for 0.5h. Continue to keep warm and add 9.48g of sodium nitrite aqueous solution (40% aqueous solution) dropwise, and stir until the reaction is completed. The organic layer is purified by solvent removal to obtain the target product 10.6g of ethyl 2-chloro-3-hydroxy-3-phenyl-2-(3-(nitro)benzyl)acrylate, with a yield of 73%.

[0116] Example 8: Preparation of 2-benzyl-2-chloro-3-hydroxy-3-(3-trifluoromethylphenyl)propionic acid

[0117] Add 12.3 g of 2-(hydroxy(3-trifluoromethyl-phenyl)methyl)acrylic acid, 25 g of acetone, 4.7 g of aniline, and 0.1 g of cuprous chloride to the reactor and stir to mix evenly. Control the temperature of the reaction liquid to 10°C, drop 15.2 g of 30% hydrochloric acid aqueous solution, then drop 9.48 g of sodium nitrite aqueous solution (40% aqueous solution), and stir until the reaction is completed. The organic layer is desolventized and purified to obtain 13.46 g of the product 2-benzyl-2-chloro-3-hydroxy-3-(3-trifluoromethylphenyl)propionic acid, with a yield of 75%.

[0118] Example 9: Preparation of 2-chloro-3-hydroxy-3-(3-pyridyl)-2-(3-trifluoromethylphenyl)propionic acid

[0119] Add 3.8g of 2-(hydroxy(3-pyridyl)methyl)acrylic acid, 18g of acetone, 3.2g of m-trifluoromethylaniline, and 0.1g of cuprous chloride to the reactor and stir to mix evenly. Control the temperature of the reaction liquid to 10°C, drop 6g of 30% hydrochloric acid aqueous solution, then drop 3.8g of sodium nitrite aqueous solution (40% aqueous solution), and stir until the reaction is completed. The organic layer is desolventized and purified to obtain 4.9g of the product 2-chloro-3-hydroxy-3-(3-pyridyl)-2-(3-trifluoromethylphenyl)propionic acid, with a yield of 68%.

[0120] ESI-MS m / z:[MH] - =358.15

[0121] ESI-MS m / z:[M+H] + =359.99

[0122] Example 10: Preparation of 1-phenyl-3-(3-(trifluoromethyl)phenyl)-2-propanone

[0123] Add 25g of 2-chloro-3-hydroxy-3-phenyl-2-(3-(trifluoromethyl)benzyl)propionic acid and 50g of methanol to the reactor. Add 40g of 30% aqueous sodium hydroxide solution at 15-20°C and stir for 0.5h. Desolventize the reaction solution, add 50g of toluene, acidify the water layer, separate the organic layer for desolventization, and add 30g of DMF for dilution. Add the solution dropwise to 32g of 5% MgCl2 / DMF solution preheated to 130-150°C. After the reaction is completed, the target product 1-phenyl-3-(3-(trifluoromethyl)phenyl)-2-propanone 18.1g is obtained with a yield of 93%.

[0124] Example 11: Preparation of 1-phenyl-3-(3-(nitro)phenyl)-2-propanone

[0125] Add 8.6g of 2-chloro-3-hydroxy-3-phenyl-2-(3-(nitro)benzyl)propionic acid and 20g of methanol to the reactor. Add 12g of 30% aqueous sodium hydroxide solution dropwise at 15-20°C and stir for 0.5h. Desolventize the reaction solution, add 30g of toluene, acidify the aqueous layer, separate the organic layer for desolventization, and add 15g of DMF for dilution. Add the solution dropwise to 16g of 5% MgCl2 / DMF solution preheated to 130-150°C. After the reaction is completed, the target product 1-phenyl-3-(3-(nitro)phenyl)-2-propanone 3.93g is obtained with a yield of 60%.

[0126]

[0127] 1 H NMR (500Hz, CDCl3) δ8.11-7.17(m,9H),3.84(s,2H),3.80(s,2H).

[0128] Example 12: Preparation of 1-phenyl-3-(3-(trifluoromethyl)phenyl)-2-propanone

[0129] Add 25g of 2-benzyl-2-chloro-3-hydroxy-3-(3-trifluoromethylphenyl)propionic acid and 50g of methanol to the reactor, and then add 40g of 30% sodium hydroxide aqueous solution dropwise at 15-20°C. After stirring for 0.5h, the reaction solution is desolvated. Add 50g of toluene, acidify the water layer, separate the organic layer for desolvation, and add 30g of DMF solvent for dilution. Then, add the solution dropwise to a 32g 5% MgCl2 / DMF solution preheated to 130-150°C. After the reaction is completed, the 1-phenyl-3-(3-(trifluoromethyl)phenyl)-2-propanone is obtained by treatment, with a yield of 90%.

[0130] Example 13: 1-(3-pyridyl)-3-(3-(trifluoromethyl)phenyl)-2-propanone

[0131] Add 18g of 2-chloro-3-hydroxy-3-pyridinyl-2-(3-(trifluoromethyl)benzyl)propionic acid and 50g of methanol to the reactor, and then add 13.3g of 30% sodium hydroxide aqueous solution dropwise at 15-20°C. After stirring for 0.5h, the reaction solution is desolvated. Add 50g of toluene, acidify the aqueous layer, separate the organic layer for desolvation, and add 30g of DMF solvent for dilution. Then, add the solution dropwise to a 31g 5% MgCl2 / DMF solution preheated to 130-150°C. After the reaction is completed, treat 1-(3-pyridinyl)-3-(3-(trifluoromethyl)phenyl)-2-acetone to obtain 13g, with a yield of 93%.

[0132]

[0133] 1 H NMR (500Hz, DMSO-d6) δ7.57(d,J=7.8Hz,1H),7.33(dd,J=13.4,6.3Hz,3H),7.28–7.15(m,4H),3.93(s,2H),3.90(s,2H).

[0134] Example 14: Preparation of 2-(hydroxy(phenyl)methyl)acrylonitrile

[0135] 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 reactor 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 target product 2-(hydroxy(phenyl)methyl)acrylonitrile, with a yield of 97%.

[0136] Example 15: Preparation of methyl 2-(hydroxy(phenyl)methyl)acrylate

[0137] Add 106g of benzaldehyde, 94.6g of methyl acrylate, 56g of DABCO to the reactor, 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 the target product methyl 2-(hydroxy(phenyl)methyl)acrylate, with a yield of 99%.

[0138] Example 16: Preparation of ethyl 2-(hydroxy(phenyl)ethyl)acrylate

[0139] Add 106g of benzaldehyde, 110g of ethyl acrylate, 56g of DABCO, and 100g of methanol to the reactor, 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 197g of the target product ethyl 2-(hydroxy(phenyl)ethyl)acrylate, with a yield of 96%.

[0140] Example 17: Preparation of methyl 2-(hydroxy(phenyl)methyl)acrylate

[0141] Add 106g of benzaldehyde, 94.6g of methyl acrylate, 61g of DMAP to the reactor, 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 173g of the target product methyl 2-(hydroxy(phenyl)methyl)acrylate, with a yield of 90%.

[0142] Example 18: Preparation of methyl 2-(hydroxy(phenyl)methyl)acrylate

[0143] Add 106g of benzaldehyde, 94.6g of methyl acrylate, 76g of DBU to the reactor, 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 182g of the target product methyl 2-(hydroxy(phenyl)methyl)acrylate, with a yield of 95%.

[0144] Example 19: Preparation of methyl 2-(hydroxy(phenyl)methyl)acrylate

[0145] Add 106g of benzaldehyde, 94.6g of methyl acrylate, 115g of trimethylamine, and 100g of methanol to the reactor, 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 184.9g of the target product methyl 2-(hydroxy(phenyl)methyl)acrylate, with a yield of 96.3%.

[0146] Example 20: Preparation of methyl 2-(hydroxy(phenyl)methyl)acrylate

[0147] Add 106g of benzaldehyde, 94.6g of methyl acrylate, 61g of DMAP to the reactor, 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 the target product methyl 2-(hydroxy(phenyl)methyl)acrylate, with a yield of 97.2%.

[0148] Example 21: Preparation of 2-(Hydroxy(phenyl)methyl)acrylamide

[0149] Add 106g of benzaldehyde, 78.2g of acrylamide, 56g of DABCO, and 100g of methanol-water mixed solvent (methanol: water = 70:30) to the reactor, 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 target product 2-(hydroxy(phenyl)methyl)acrylamide, with a yield of 70%.

[0150] Example 22: Preparation of methyl 2-(hydroxy(3-pyridyl)methyl)acrylate

[0151] Add 10.7 g of pyridine carboxaldehyde, 9.5 g of methyl acrylate, and 5.6 g of DABCO to the reactor 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 target product 2-(hydroxy(3-pyridyl)methyl)acrylate 18.2 g is obtained, with a yield of 94.3%.

[0152] Example 23 Preparation of 2-(hydroxy(pyridyl)methyl)acrylic acid

[0153] Add 7.7 g of methyl 2-(hydroxy(pyridyl)methyl)acrylate and 15 mL of water to the reactor and stir to mix evenly. Control the temperature to 0-30°C, drop 5.3 g of 30% sodium hydroxide aqueous solution, continue stirring until the reaction is complete, extract with toluene and separate the layers. The aqueous layer is acidified, filtered and dried to obtain 6.82 g of the target product 2-(hydroxy(pyridyl)methyl)acrylic acid, with a yield of 95.2%.

[0154] Example 24: Preparation of methyl 2-(hydroxy(3-trifluoromethyl-phenyl)methyl)acrylate

[0155] Add 34.8g of m-trifluoromethylbenzaldehyde, 17.2g of methyl acrylate, 11.2g of DABCO to the reactor, 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 the target product 2-(hydroxy(3-trifluoromethyl-phenyl)methyl)methyl acrylate 48.3g, with a yield of 93%.

[0156] Example 25: Preparation of methyl 2-(hydroxymethyl)acrylate

[0157] Add 50g of formaldehyde (37% aqueous solution), 53g of methyl acrylate, 34g of DABCO, and 50g of methanol to the reactor 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 target product 2-(hydroxymethyl) methyl acrylate 42.4g is obtained, with a yield of 60%.

[0158] Example 26: Preparation of ethyl 2-(hydroxymethyl)acrylate

[0159] Add 98g of formaldehyde (37% aqueous solution), 102g of ethyl acrylate, 56g of DABCO, and 100g of methanol to the reactor 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 target product 2-(hydroxymethyl) ethyl acrylate 91g is obtained, with a yield of 69%.

[0160] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical solutions and inventive concepts of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A method for preparing a 1,3-disubstituted-2-acetone compound I, characterized in that: Compound II, compound III and a diazotizing agent react under the action of catalyst 1 to obtain compound IV, and compound IV reacts to obtain compound I. The reaction formula is as follows: Wherein, Ar is any one of an unsubstituted or substituted C6-C12 aryl group, an unsubstituted or substituted heteroaryl group containing 1-4 atoms selected from nitrogen, oxygen, and sulfur atoms; R is any one of hydrogen, an unsubstituted or substituted C1-C10 alkyl group, an unsubstituted or substituted C6-C12 aryl group, and an unsubstituted or substituted heteroaryl group containing 1-4 atoms selected from nitrogen, oxygen, and sulfur atoms; EWG is -CN or -COR 2 Any one of R 2 is unsubstituted or substituted amino or -OR 3 , the R 3 Any one of hydrogen, unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C6-C12 aryl, and unsubstituted or substituted heteroaryl containing 1-4 atoms selected from nitrogen, oxygen, and sulfur atoms; The heteroaryl group is an unsubstituted or substituted five-membered or six-membered heteroaryl group; The substituent is halogen, hydroxyl, CN, COOH, CONH2, NO2, NH2, CF 3； X is any one of halogen, nitrate, sulfate or sulfite; The diazotizing agent includes alkali metal nitrite, nitrite ester, nitrosyl sulfuric acid, and nitrous acid gas; The catalyst 1 is a metal halide or a metal sulfate; The compound IV is prepared into the compound I under the catalytic action of the acid or base 2 under the condition of the base 1; The base 1 is any one or more of alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal carbonate, and alkaline earth metal carbonate; The acid is any one of a Lewis acid or a protonic acid; the Lewis acid is AlCl3, FeCl3, SbCl5, SnCl4, BCl3, TiCl4, ZnCl2, MgCl2; the protonic acid is fluoric acid, sulfuric acid, phosphoric acid; The base 2 is any one or more of alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, and alkaline earth metal carbonates.

2. The method for preparing 1,3-disubstituted-2-acetone compounds according to claim 1, characterized in that: Ar is phenyl or n is an integer from 1 to 5. When n is an integer not less than 2, multiple R 1 Can be the same or different; R is any one of an unsubstituted or substituted phenyl group, an unsubstituted or substituted heteroaryl group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur atoms; R 2 is a mono- or di-substituted amino group; R 3 Any one of unsubstituted or substituted C1-C8 alkyl, unsubstituted or substituted C6-C8 aryl, and unsubstituted or substituted heteroaryl containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur atoms; X is Cl.

3. The method for preparing 1,3-disubstituted propan-2-one compounds according to claim 2, characterized in that: R1 is any one of a substituted alkyl group and a nitro group, and n is 1; R is any one of nitro, halogen-substituted C1-C10 alkyl, phenyl substituted by one or more, and unsubstituted or substituted pyridine; The R 3 It is any of methyl and ethyl.

4. The method for preparing 1,3-disubstituted propan-2-one compounds according to any one of claims 1 to 3, characterized in that: The molar ratio of the diazotizing agent to the compound III is 1:2-1; the metal in the catalyst 1 is copper; and the base 2 is any one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate.

5. The method for preparing 1,3-disubstituted-2-acetone compounds according to claim 4, characterized in that: The diazotizing agent is an alkali metal nitrite, and the molar ratio of the diazotizing agent to the compound III is 0.5-2:1; the catalyst 1 is cuprous chloride or copper sulfate; and the Lewis acid is AlCl3.

6. The method for preparing 1,3-disubstituted-2-acetone compounds according to claim 5, characterized in that: The alkali metal nitrite is sodium nitrite.

7. An intermediate IV, having the chemical structural formula: in, Ar is any one of an unsubstituted or substituted C6-C12 aryl group, an unsubstituted or substituted heteroaryl group containing 1-4 atoms selected from nitrogen, oxygen, and sulfur atoms; R is any one of hydrogen, unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C6-C12 aryl, and unsubstituted or substituted heteroaryl containing 1-4 atoms selected from nitrogen, oxygen, and sulfur atoms; EWG is -CN or -COR 2 Any one of R 2 is unsubstituted or substituted amino or -OR 3 , the R 3 Any one of hydrogen, unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C6-C12 aryl, and unsubstituted or substituted heteroaryl containing 1-4 atoms selected from nitrogen, oxygen, and sulfur atoms; X is any one of chlorine, bromine, iodine, nitrate, sulfate or sulfite; When R is a substituted alkyl group, R is not a substituted cyclopropyl group, an unsubstituted or substituted ethyl difluoroacetate alkyl group, or an unsubstituted or substituted difluoroamido alkyl group; The substituents are halogen, hydroxyl, CN, COOH, CONH2, NO2, NH2, CF3.

8. The method for preparing 1,3-disubstituted-2-acetone compounds according to claim 1, characterized in that: Compound II is prepared by coupling reaction of compound V with compound VI in the presence of catalyst 2, and the reaction formula is as follows: R is any one of hydrogen, unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C6-C12 aryl, and unsubstituted or substituted heteroaryl containing 1-4 atoms selected from nitrogen, oxygen, and sulfur atoms; EWG is -CN or -COR 2 Any one of R 2 is unsubstituted or substituted amino or -OR 3 , the R 3 is any one of hydrogen, unsubstituted or substituted C1-C10 alkyl, unsubstituted or substituted C6-C12 aryl, unsubstituted or substituted heteroaryl containing 1-4 atoms selected from nitrogen, oxygen and sulfur atoms; the catalyst 2 is any one of organic amine or organic phosphine The substituents are halogen, hydroxyl, CN, COOH, CONH2, NO2, NH2, CF3.

9. The method for preparing 1,3-disubstituted-2-acetone compounds according to claim 8, characterized in that: The catalyst 2 is any one of DABCO, DMAP, DBU or trimethylamine; the molar ratio of the compound V to the catalyst 2 is 1-15:

1.

10. The method for preparing 1,3-disubstituted-2-acetone compounds according to claim 9, characterized in that: The molar ratio of the compound V to the catalyst 2 is 1-10:1.

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