Carboxymethyl ketone compounds and their preparation methods

Abstract

The present application discloses a method for preparing carboxymethyl ketone compounds, comprising: reacting a carboxylic acid compound, a sulfonium ylide compound and a ligand in a solvent in the presence of an iridium catalyst to prepare the carboxymethyl ketone compounds. The present application realizes the reaction of the carboxylic acid compound and the sulfonium ylide compound in the presence of an iridium catalyst, and successfully introduces a heterocycle during the reaction to generate various heterocyclic carboxymethyl ketone compounds. This method has the characteristics of cheap and easily available raw materials, a wide variety of carboxylic acids used, easy separation of the obtained target products, high yield, simple reaction operation, wide applicability, etc., and solves the problems of low yield, low selectivity, narrow functional group compatibility, complex operation, use of excessive oxidants, etc. existing in other synthesis methods.

Description

Technical Field

[0001] This application relates to the technical field of organic synthesis, and more particularly, to carboxymethyl ketone compounds and their preparation methods. Background Art

[0002] Carboxymethyl ketone compounds are widely present in natural products, bioactive molecules, pesticides, and many synthetic intermediates. Among them, heterocyclic carboxymethyl ketone compounds, as an important structural unit in medicinal chemistry, not only have excellent biological activities, such as good pharmacological activities, including anti-inflammatory, antihypertensive, antitumor, enzyme inhibitor, etc., but also have variable chemical structures, which are the hotspots and difficulties in organic chemical synthesis research.

[0003] The traditional method for synthesizing carboxymethyl ketone compounds is through the oxidative coupling reaction of ketones and carboxylic acids. These reactions often require the use of excessive strong oxidants, have a narrow substrate scope, and harsh reaction conditions. In recent years, there has been research on the method of efficiently preparing carboxymethyl ketones by the O-H bond insertion of metal-catalyzed diazo compounds and carboxylic acids. However, diazo compounds are unstable, toxic, and prone to explosion, which is not conducive to large-scale production.

[0004] In addition, there has also been research on the oxidative coupling reaction of Au-catalyzed terminal alkynes and carboxylic acids to generate Au carbenes in situ for O-H bond insertion to prepare carboxymethyl ketone compounds; and the O-H bond insertion reaction of Ru(acac) 3 catalyzing carboxylic acids and sulfur ylides. However, the above methods cannot prepare heterocyclic carboxymethyl ketones and have a narrow functional group compatibility. Recently, it has been reported that VO(acac) 2 catalyzes the reaction of carboxylic acids and sulfur ylides to prepare carboxymethyl ketone compounds, but the number of product types obtained is small, and the yields are all lower than 55%. For important active functional groups in drug molecules, such as phenolic hydroxyl groups, amino groups, indoles, alkynyl groups, alkenyl groups, etc., the target products cannot be obtained.

[0005] Therefore, how to expand the substrate scope and improve the yield remains a difficult point in the current synthesis of heterocyclic carboxymethyl ketone compounds. Summary of the Invention

[0006] To solve the above problems and increase the variety of carboxymethyl ketone compounds and improve their preparation yields, the first object of this application is to provide a method for preparing carboxymethyl ketone compounds, including:

[0007] Reacting a carboxylic acid compound, a sulfur ylide compound, and a ligand in a solvent in the presence of an iridium catalyst to prepare the carboxymethyl ketone compound;

[0008] The structure of the carboxylic acid compound is as follows:

[0009]

[0010] The structure of the sulfonium ylide compound is as follows:

[0011]

[0012] The structure of the carboxymethyl ketone compound is as follows:

[0013]

[0014] Wherein, R 1 is selected from any one of aryl, alkyl and heterocyclic group, and R 2 is selected from any one of aryl, alkyl and heterocyclic group.

[0015] In the present application, the reaction of a carboxylic acid compound and a sulfonium ylide compound is realized in the presence of an iridium catalyst, and a heterocyclic group is successfully introduced during the reaction to generate various heterocyclic carboxymethyl ketone compounds. This method has the characteristics of cheap and easily available raw materials, a wide variety of carboxylic acids used, easy separation of the obtained target products, high yield, simple reaction operation, wide applicability, etc., and solves the problems of low yield, low selectivity, narrow functional group compatibility, complex operation, use of excessive oxidants, etc. existing in other synthesis methods.

[0016] In one embodiment, the ligand is selected from at least one of triphenylphosphine, N,N,N',N'-tetramethylethylenediamine, 2,2-bipyridine and 1,10-phenanthroline.

[0017] In one embodiment, the iridium catalyst is selected from at least one of 1,5-cyclooctadiene iridium dichloride dimer, methoxy(cyclooctadiene)iridium dimer, chloro bis(cyclooctene)iridium(I) dimer and dichloro(pentamethylcyclopentadienyl)iridium(III) dimer.

[0018] In one embodiment, the sulfonium ylide compound is selected from at least one of benzoyl sulfonium ylide, 4-methylbenzoyl sulfonium ylide, 4-fluorobenzoyl sulfonium ylide, 4-iodobenzoyl sulfonium ylide, 2-thiophenecarbonyl sulfonium ylide, cyclohexylcarbonyl sulfonium ylide and cyclohexylacetyl sulfonium ylide.

[0019] In one embodiment, the carboxylic acid compound is selected from at least one of 3-indoleacetic acid, 5-fluoro-3-indoleacetic acid, 6-chloro-3-indoleacetic acid, 2-methyl-3-indoleacetic acid, 3-indolepropionic acid, 3-indolebutyric acid, 3-indolecarboxylic acid, 5-hydroxynicotinic acid, 6-aminonicotinic acid, pyrimidine-5-carboxylic acid, 4-hydroxymethylbenzoic acid, 4-vinylbenzoic acid and acetic acid.

[0020] In one embodiment, the solvent is selected from at least one of 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide and dimethyl sulfoxide.

[0021] In one embodiment, the molar ratio among the iridium catalyst, the ligand, the carboxylic acid compound and the sulfonium ylide is (0.01 - 0.05):(0.02 - 0.10):1:(1.0 - 2.0).

[0022] In one embodiment, the preparation method satisfies at least one of the following features:

[0023] (1) The reaction is carried out in an inert gas;

[0024] (2) The reaction is carried out at 90°C - 120°C for 8 - 16 h;

[0025] (3) After the reaction ends, a purification step is further included, including: after cooling the obtained reaction mixture, washing and extracting the mixture to obtain a carboxymethyl ketone compound.

[0026] The second object of the present application is to provide a carboxymethyl ketone compound prepared by the method.

[0027] In one embodiment, the chemical formula of the carboxymethyl ketone compound is shown as the following structure:

[0028]

[0029] R 1 is selected from any one of an aryl group, an alkyl group and a heterocyclic group, and R 2 is selected from any one of an aryl group, an alkyl group and a heterocyclic group.

[0030] In one embodiment, the heterocyclic group in R 1 is connected to any one of an alkyl group, a halogen group, an alkenyl group, a hydroxyl group and an amino group.

[0031] The third object of the present application is to provide the use of at least one of the above carboxymethyl ketone compound, its pharmaceutically acceptable salt, its solvate or hydrate, and the pharmaceutically acceptable salt of its solvate or hydrate in the preparation of a drug for treating diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] In order to more clearly illustrate the specific embodiments of the present application or the technical solutions in the prior art, the following will briefly introduce the drawings required for use in the description of the specific embodiments or the prior art. Obviously, the drawings in the following description are some embodiments of the present application. For those of ordinary skill in the art, other drawings can also be obtained based on these drawings without creative efforts.

[0033] Figure 1 It is a schematic diagram of the reaction principle for preparing the carboxymethyl ketone compound in the embodiment of the present application. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0034] Reference will now be made in detail to embodiments of the present application, one or more examples of which are described below. Each example is provided by way of explanation and not limitation of the present application. In fact, it will be apparent to those skilled in the art that various modifications and variations can be made to the present application without departing from the scope or spirit of the present application. For example, features described or illustrated as part of one embodiment can be used in another embodiment to yield a still further embodiment.

[0035] Accordingly, it is intended that the present application cover such modifications and variations that fall within the scope of the appended claims and their equivalents. Other objects, features, and aspects of the present application are disclosed in or are apparent from the following detailed description. Those of ordinary skill in the art should understand that this discussion is only a description of exemplary embodiments and is not intended to limit the broader aspects of the present application.

[0036] As mentioned above, there are currently problems in the synthesis of carboxymethyl ketone compounds, such as narrow substrate scope, low yield, and harsh reaction conditions.

[0037] To solve the above technical problems, a first aspect of the present application provides a method for preparing a carboxymethyl ketone compound, comprising:

[0038] Reacting a carboxylic acid compound, a sulfur ylide compound, and a ligand in a solvent in the presence of an iridium catalyst to prepare the carboxymethyl ketone compound;

[0039] The structure of the carboxylic acid compound is shown as follows:

[0040]

[0041] The structure of the sulfur ylide compound is shown as follows:

[0042]

[0043] The structure of the carboxymethyl ketone compound is shown as follows:

[0044] The structure of the carboxymethyl ketone compound is shown in Formula I:

[0045]

[0046] Wherein, R 1 is selected from any one of aryl, alkyl, and heterocyclic groups, and R 2 is selected from any one of aryl, alkyl, and heterocyclic groups.

[0047] It should be noted that the iridium catalyst can form an iridium carbene intermediate with the sulfur ylide. The present application for the first time discovers that this iridium carbene intermediate can undergo an O-H bond insertion reaction with carboxylic acid compounds, thereby realizing the preparation of various different types of carboxymethyl ketone compounds, especially various heterocyclic carboxymethyl ketone compounds, under mild conditions. The preparation method of the carboxymethyl ketone compounds in the present application has the characteristics of inexpensive and easily available raw materials, a wide variety of carboxylic acids used, easy separation of the target products obtained, high yield, simple reaction operation, wide applicability, etc., and solves the problems of low yield, low selectivity, narrow functional group compatibility, complex operation, use of excessive oxidants, etc. existing in other synthesis methods.

[0048] In some embodiments, the heterocyclic group of R1 in the carboxymethyl ketone compounds of the present application is connected to any one of an alkyl group, a halogen group, an alkenyl group, a hydroxyl group, and an amino group. Therefore, the preparation method of the present application can be compatible with important functional groups such as hydroxyl group, amino group, indole, etc., and the product has a high yield and has potential application prospects in pesticides and bioactive drugs.

[0049] As used herein, the term "alkyl group" refers to a monovalent residue formed by removing a hydrogen atom from a saturated hydrocarbon containing primary (normal) carbon atoms, or secondary carbon atoms, or tertiary carbon atoms, or quaternary carbon atoms, or a combination thereof, including straight-chain alkyl groups and cycloalkyl groups. A phrase containing this term, for example, "C 1 ~ 9 straight-chain alkyl group" refers to an alkyl group containing 1 to 9 carbon atoms, and each occurrence may independently be a C 1 straight-chain alkyl group, C 2 alkyl group, C 3 straight-chain alkyl group, C 4 straight-chain alkyl group, C 5 straight-chain alkyl group, C 6 straight-chain alkyl group, C 7 straight-chain alkyl group, C 8 straight-chain alkyl group or C 9 straight-chain alkyl group. Suitable examples include, but are not limited to: methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), 1-propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, i-propyl, -CH(CH 3 ) 2 ), 1-butyl (n-Bu, n-butyl, -CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propyl (i-Bu, i-butyl, -CH 2 CH(CH3 ) 2 )、2-butyl (s-Bu, sec-butyl, -CH(CH 3 )CH 2 CH 3 ))、2-methyl-2-propyl (t-Bu, tert-butyl, -C(CH 3 ) 3 )、1-pentyl (n-pentyl, -CH 2 CH 2 CH 2 CH 2 CH 3 ))、2-pentyl (-CH(CH3)CH2CH2CH3)、3-pentyl (-CH(CH 2 CH 3 )) 2 )、2-methyl-2-butyl (-C(CH 3 ) 2 CH 2 CH 3 ))、3-methyl-2-butyl (-CH(CH 3 )CH(CH 3 )) 2 )、3-methyl-1-butyl (-CH 2 CH 2 CH(CH 3 )) 2 )、2-methyl-1-butyl (-CH 2 CH(CH 3 )CH 2 CH 3 ))、1-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ))、2-hexyl (-CH(CH 3 )CH 2 CH 2 CH 2 CH 3 ))、3-hexyl (-CH(CH 2 CH 3 )(CH 2 CH 2 CH 3 ))、2-methyl-2-pentyl (-C(CH 3 )) 2 CH 2 CH 2 CH 3 ))、3-methyl-2-pentyl (-CH(CH 3)CH(CH 3 )CH 2 CH 3 )、4-methyl-2-pentyl (-CH(CH 3 )CH 2 CH(CH 3 ) 2 )、3-methyl-3-pentyl (-C(CH 3 )(CH 2 CH 3 ) 2 )、2-methyl-3-pentyl (-CH(CH 2 CH 3 )CH(CH 3 ) 2 )、2,3-dimethyl-2-butyl (-C(CH 3 ) 2 CH(CH 3 ) 2 )、3,3-dimethyl-2-butyl (-CH(CH 3 )C(CH 3 ) 3 and octyl (-(CH 2 ) 7 CH 3 )。

[0050] The term "cycloalkyl" refers to a monovalent residue formed by removing a hydrogen atom from a non-aromatic hydrocarbon containing ring carbon atoms, and can be a monocycloalkyl, or a spirocycloalkyl, or a bridged cycloalkyl. A phrase containing this term, for example, "C 3 ~C 9 cycloalkyl" refers to a cycloalkyl containing 3 to 9 carbon atoms, and each occurrence can independently be C 3 cycloalkyl, C 4 cycloalkyl, C 5 cycloalkyl, C 6 cycloalkyl, C 7 cycloalkyl, C 8 cycloalkyl or C 9 cycloalkyl. Suitable examples include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Additionally, "cycloalkyl" may also contain one or more double bonds, and representative examples of cycloalkyls containing double bonds include cyclopentenyl, cyclohexenyl, cyclohexadienyl and cyclobutadienyl.

[0051] "Alkenyl" refers to a monovalent residue formed by removing a hydrogen atom from a hydrocarbon containing at least one unsaturated site, i.e., a carbon-carbon sp 2 double bond. A phrase containing this term, for example, "C 2 ~C 9"Alkenyl" refers to an alkenyl group containing 2 to 9 carbon atoms, and each occurrence can independently be C 2 alkenyl, C 3 alkenyl, C 4 alkenyl, C 5 alkenyl, C 6 alkenyl, C 7 alkenyl, C 8 alkenyl or C 9 alkenyl. Suitable examples include, but are not limited to: vinyl (-CH=CH 2 ), allyl (-CH 2 CH=CH 2 ), cyclopentenyl (-C 5 H 7 ), and 5-hexenyl (-CH 2 CH 2 CH 2 CH 2 CH=CH 2 ).

[0052] In this text, the term "aryl" refers to an aromatic hydrocarbon group derived by removing one hydrogen atom from an aromatic ring compound, and can be a monocyclic aryl group, or a fused-ring aryl group, or a polycyclic aryl group. For polycyclic ring systems, at least one is an aromatic ring system. For example, "C 5 ~C 10 aryl" refers to an aryl group containing 5 to 10 carbon atoms, and each occurrence can independently be C 5 aryl, C 6 aryl, C 7 aryl, C 8 aryl, C 9 aryl or C 10 aryl. Suitable examples include, but are not limited to: benzene, biphenyl, naphthalene, anthracene, phenanthrene, coronene, triphenylene, and their derivatives.

[0053] In this text, the heterocyclic group includes any one of heteroalkyl and heteroaryl.

[0054] In this text, heteroalkyl refers to a cycloalkyl group in which at least one carbon atom is replaced by a non-carbon atom, and the non-carbon atom can be an N atom, an O atom, an S atom, etc., and can be a saturated ring or a partially unsaturated ring. Phrases containing this term, for example, "C 4 ~C 9 heteroalkyl" refers to a heteroalkyl group containing 4 to 9 carbon atoms, and each occurrence can independently be C 4 heteroalkyl, C 5 heteroalkyl, C 6 heteroalkyl, C 7 heteroalkyl, C 8 heteroalkyl or C 9Heteroalkyl. Suitable examples include, but are not limited to: dihydropyridyl, tetrahydropyridyl (piperidyl), tetrahydrothienyl, sulfoxidized tetrahydrothienyl, tetrahydrofuryl, tetrahydroquinolyl, tetrahydroisoquinolyl, dihydroindolyl.

[0055] As used herein, the term "heteroaryl" means that at least one carbon atom in the aryl group is replaced by a non-carbon atom, and the non-carbon atom can be an N atom, an O atom, an S atom, etc. For example, "C 3 ~C 10 heteroaryl" means a heteroaryl containing 3 to 10 carbon atoms, and each occurrence can be independently C 3 heteroaryl, C 4 heteroaryl, C 5 heteroaryl, C 6 heteroaryl, C 7 heteroaryl, C 8 heteroaryl, C 9 heteroaryl or C 10 heteroaryl. Suitable examples include, but are not limited to: furan, benzofuran, thiophene, benzothiophene, pyrrole, pyrazole, triazole, imidazole, oxazole, oxadiazole, thiazole, tetrazole, indole, carbazole, pyrroloimidazole, pyrrolopyrrole, thiophenopyrrole, thiophenothiophene, furanopyrrole, furanofuran, thiophenofuran, benzisoxazole, benzisothiazole, benzimidazole, pyridine and pyrazine, pyridazine, pyrimidine, triazine, quinoline, isoquinoline, phthalazine, quinoxaline, phenanthridine, peridine, quinazoline and quinazolinone.

[0056] "Amino" means a residue formed by an amine losing at least one hydrogen atom, and can be a primary amino group, a secondary amino group or a tertiary amino group. Taking a monovalent amino group as an example, it has the structural feature of the formula -N(X) 2 , where each "X" is independently H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, etc. Non-limiting types of amino groups include -NH 2 , -N(alkyl) 2 , -NH(alkyl), -N(cycloalkyl) 2 , -NH(cycloalkyl), -N(heterocyclic group) 2 , -NH(heterocyclic group), -N(aryl) 2 , -NH(aryl), -N(alkyl)(aryl), -N(alkyl)(heterocyclic group), -N(cycloalkyl)(heterocyclic group), -N(aryl)(heteroaryl), -N(alkyl)(heteroaryl), etc.

[0057] "Halogen" or "halo group" means F, Cl, Br or I.

[0058] In a chemical reaction, ligands can often enhance the activity of catalysts, lower the reaction activation energy, accelerate the reaction rate, and thus increase the reaction yield. To achieve the preparation of carboxymethyl ketone compounds, the ligands of the present application are selected from at least one of triphenylphosphine, N,N,N',N'-tetramethylethylenediamine, 2,2-bipyridine, and 1,10-phenanthroline.

[0059] In some embodiments, to form a metal carbene intermediate with the sulfonium ylide compound, the iridium catalyst is selected from at least one of dichloro(1,5-cyclooctadiene)iridium dimer, methoxy(cyclooctadiene)iridium dimer, dichloro(cyclooctene)iridium(I) dimer, and dichloro(pentamethylcyclopentadienyl)iridium(III) dimer.

[0060] In some embodiments, the sulfonium ylide compound is selected from at least one of benzoyl sulfonium ylide, 4-methylbenzoyl sulfonium ylide, 4-fluorobenzoyl sulfonium ylide, 4-iodobenzoyl sulfonium ylide, 2-thiophenecarbonyl sulfonium ylide, cyclohexylcarbonyl sulfonium ylide, and cyclohexylacetyl sulfonium ylide.

[0061] In some embodiments, the carboxylic acid compound is selected from at least one of 3-indoleacetic acid, 5-fluoro-3-indoleacetic acid, 6-chloro-3-indoleacetic acid, 2-methyl-3-indoleacetic acid, 3-indolepropionic acid, 3-indolebutyric acid, 3-indolecarboxylic acid, 5-hydroxynicotinic acid, 6-aminonicotinic acid, pyrimidine-5-carboxylic acid, 4-hydroxymethylbenzoic acid, 4-vinylbenzoic acid, and acetic acid.

[0062] In some embodiments, the solvent is selected from at least one of 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, and dimethyl sulfoxide, and is used to dissolve each reactant to form the target product heterocyclic carboxymethyl ketone compounds.

[0063] In some embodiments, to improve the utilization rate of raw materials, the molar ratio of the iridium catalyst, ligand, carboxylic acid compound, and sulfonium ylide is (0.01 - 0.05):(0.02 - 0.10):1:(1.0 - 2.0).

[0064] In some embodiments, to ensure the smooth progress of the reaction, the reaction of the present application is carried out in an inert gas to avoid other side reactions under aerobic conditions. The inert gas of the present application is an inert gas conventionally used in the art and can be nitrogen, argon, etc.

[0065] To obtain a higher yield of the target product, the reaction conditions of this application are to react at 90°C to 120°C for 8 to 16 hours. Further, the reaction conditions of this application are to react at 100°C to 120°C for 8 to 12 hours. Furthermore, the reaction conditions of this application are to react at 110°C to 120°C for 8 to 10 hours. Therefore, this application has the advantages of mild reaction conditions, simple reaction operation, and high product yield.

[0066] In some embodiments, after the reaction is completed, a purification step is further included, including: after cooling the reaction mixture, washing and extracting the mixture to obtain a carboxymethyl ketone compound.

[0067] Specifically, cooling the reaction mixture means cooling the reaction mixture to room temperature after the reaction is completed. Further, washing with a saturated ammonium chloride solution is beneficial for extraction and separation, extracting the target product with an extraction solvent to obtain an extraction mixture, drying the extraction mixture with a desiccant, and then concentrating by reduced pressure distillation to remove the extraction solvent to obtain a crude product, and separating the crude product by column chromatography to obtain the target product.

[0068] More specifically, the extraction solvent is selected from at least one of ethyl acetate and dichloromethane. The desiccant is selected from at least one of anhydrous sodium sulfate and anhydrous magnesium sulfate.

[0069] Correspondingly, according to the above preparation method, the second aspect of this application is to provide a carboxymethyl ketone compound prepared by the above method.

[0070] The third aspect of this application provides the use of at least one of the above carboxymethyl ketone compound, its pharmaceutically acceptable salt, its solvate or hydrate, and its pharmaceutically acceptable salt of the solvate or hydrate in the preparation of a disease treatment drug.

[0071] As used herein, the term "pharmaceutically acceptable" refers to those ligands, materials, compositions, and / or dosage forms that are suitable for administration to a patient within the scope of reasonable medical judgment and are commensurate with a reasonable benefit / risk ratio.

[0072] "Pharmaceutically acceptable salts" refer to salts formed by any of the compounds in the indicated structure with acids or bases that are suitable for use as drugs. Pharmaceutically acceptable salts include inorganic salts and organic salts. Among them, one type of salt is the salt formed by the compounds of the present invention with acids. Acids suitable for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, glutamic acid. Another type of salt is the salt formed by the compounds of the present invention with bases. Bases suitable for forming salts include, but are not limited to: alkali metal salts (such as sodium salts or potassium salts), alkaline earth metal salts (such as magnesium salts or calcium salts), ammonium salts (such as lower alkanolammonium salts and other pharmaceutically acceptable amine salts), such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed by morpholine, piperazine, and lysine, respectively.

[0073] "Solvate" refers to a complex formed by coordination of a compound represented by General Formula I with solvent molecules in a specific ratio. "Hydrate" refers to a complex formed by coordination of the compound of the present invention with water.

[0074] In some embodiments, the above-mentioned disease treatment drugs further include a pharmaceutically acceptable carrier for realizing the pharmacological activities of the carboxymethyl ketone compounds of the present application, including anti-inflammatory, antihypertensive, antitumor, enzyme activity inhibition, etc.

[0075] "Pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. As used herein, the language "pharmaceutically acceptable carrier" includes buffers, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like that are compatible with the administration of the drug. Each carrier must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients in the formulation and not harmful to the patient. Suitable examples include, but are not limited to: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch, potato starch and substituted or unsubstituted β-cyclodextrin; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0076] Application method

[0077] There are no particular limitations on the dosage form and administration route of the carboxymethyl ketone compounds or their pharmaceutical compositions of the present application.

[0078] Representative administration routes include, but are not limited to: oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) injection, and topical administration.

[0079] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier) such as sodium citrate or calcium phosphate dibasic, or with the following components: (a) fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders such as hydroxypropylmethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants such as glycerol; (d) disintegrants such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers such as paraffin; (f) absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also contain buffering agents. Solid dosage forms such as tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and release of the active compound or compounds in such compositions may be delayed in a portion of the digestive tract in a manner that releases the compound or compounds. Examples of embedding components that may be used are polymeric and wax-like substances. If necessary, the active compound may also be in the form of microcapsules with one or more of the above excipients.

[0080] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as water or other solvents, solubilizers, and emulsifying agents, specifically, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3 - butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances. In addition to these inert diluents, the composition may also contain adjuvants such as wetting agents, emulsifying agents, and suspending agents, sweetening agents, flavoring agents, and perfumes. For example, suspensions may contain suspending agents such as ethoxylated isooctadecanol, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, and agar, or mixtures of these substances.

[0081] Compositions for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous or non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0082] Dosage forms for topical administration include ointments, powders, patches, sprays, and inhalants. They are prepared by mixing the active ingredient with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants that may be required under sterile conditions.

[0083] As used herein, "drug" includes any medicament, compound, composition, or mixture that provides a physiological and / or pharmacological effect, either in vivo or in vitro, and typically provides a beneficial effect. There is no particular limitation on the range of physiological and / or pharmacological effects produced by the "drug" in vivo, which can be a systemic effect or only a local effect. There is no particular limitation on the activity of the "drug", which can be an active substance that can interact with other substances or an inert substance that does not interact.

[0084] As used herein, "therapeutically effective amount" refers to the amount of the compound of the present invention that will elicit a biological or medical response in an individual, for example, the amount of the compound of the present invention that brings about a positive physiological and / or pharmacological effect in the individual. Positive physiological and / or pharmacological effects include, but are not limited to, reducing or inhibiting enzyme or protein activity, or improving symptoms, alleviating diseases, slowing or delaying the disease process, or preventing diseases, etc.

[0085] The embodiments of the present application will be described in detail below in conjunction with examples, but the present application is not limited to these examples. The test methods used in the following examples are all conventional methods unless otherwise specified; the materials, reagents, etc. used are commercially available reagents and materials unless otherwise specified.

[0086] The embodiments of the present application are based on Figure 1 the reaction principle shown, and 19 carboxymethyl ketone compounds with different structures were prepared, and most of the yields were above 70%. The preparation method of the present application has the characteristics of inexpensive and easily available raw materials, a wide variety of carboxylic acids used, easy separation of the obtained target products, compatibility with important active functional groups, high yield, simple reaction operation, wide applicability, etc., and solves the problems of low yield, low selectivity, narrow functional group compatibility, complex operation, use of excessive oxidants, etc. existing in other synthesis methods.

[0087] Example 1

[0088] This example provides a heterocyclic carboxymethyl ketone compound: 2-oxo-2-phenethyl-2-(1H-indol-3-yl) acetate, and the specific structure is shown as follows:

[0089]

[0090] This example provides a preparation method of 2-oxo-2-phenethyl-2-(1H-indol-3-yl) acetate, including:

[0091] Add 0.1 mmol of 3-indoleacetic acid, 0.20 mmol of benzoyl sulfonium ylide, 0.003 mmol of dichloro(1,5-cyclooctadiene)iridium(III) dimer, 0.006 mmol of 1,10-phenanthroline, and 0.5 mL of DMF solvent into a reactor. Under a nitrogen atmosphere, heat to 110 °C and continuously stir for 12 h. Stop the reaction, cool to room temperature, wash with saturated ammonium chloride solution, extract with dichloromethane, dry, and remove the solvent by distillation under reduced pressure. The crude product is separated by column chromatography to obtain the target product with a yield of 90%.

[0092] The nuclear magnetic resonance hydrogen spectrum information of the target product in this example is specifically as follows: 1 H NMR(500MHz,CDCl 3 ):δ8.14(br s,1H),7.89(d,J=7.7Hz,2H),7.66(d,J=7.8Hz,1H),7.59(t,J=7.4Hz,1H),7.46(t,J=7.4Hz,2H),7.36(d,J=8.0Hz,1H),7.25(s,1H),7.21(t,J=7.5Hz,1H),7.15(t,J=7.4Hz,1H),5.36(s,2H),3.98(s,2H).

[0093] Example 2

[0094] This example provides a heterocyclic carboxymethyl ketone compound: 2-oxo-2-phenethyl 2-(5-fluoro-1H-indol-3-yl)acetate, and the specific structure is as follows:

[0095]

[0096] This example provides a preparation method of 2-oxo-2-phenethyl 2-(5-fluoro-1H-indol-3-yl)acetate, including:

[0097] Add 0.1 mmol of 5-fluoro-3-indoleacetic acid, 0.20 mmol of benzoyl sulfonium ylide, 0.003 mmol of dichloro(1,5-cyclooctadiene)iridium(III) dimer, 0.006 mmol of 2,2'-bipyridine, and 0.5 mL of DMF solvent into a reactor. Under a nitrogen atmosphere, heat to 100 °C and continuously stir for 16 h. Stop the reaction, cool to room temperature, wash with saturated ammonium chloride solution, extract with dichloromethane, dry, and remove the solvent by distillation under reduced pressure. The crude product is separated by column chromatography to obtain the target product with a yield of 68%.

[0098] The nuclear magnetic resonance hydrogen spectrum information of the target product in this example is specifically as follows: 1 H NMR(600MHz,CDCl 3): δ 8.43 (br s, 1H), 7.87 (d, J = 7.2 Hz, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.8 Hz, 2H), 7.31–7.23 (m, 1H), 7.17 (dd, J = 8.8, 4.3 Hz, 1H), 7.09 (s, 1H), 6.93–6.83 (m, 1H), 5.36 (s, 2H), 3.88 (s, 2H).

[0099] Example 3

[0100] This example provides a heterocyclic carboxymethyl ketone compound: 2-oxo-2-phenethyl 2-(6-chloro-1H-indol-3-yl)acetate, and the specific structure is as follows:

[0101]

[0102] This example provides a preparation method of 2-oxo-2-phenethyl 2-(6-chloro-1H-indol-3-yl)acetate, including:

[0103] Add 0.1 mmol of 6-chloro-3-indoleacetic acid, 0.15 mmol of benzoyl sulfonium ylide, 0.004 mmol of dichloroiridium(III) dimer of 1,5-cyclooctadiene, 0.006 mmol of 1,10-phenanthroline, and 0.5 mL of DMF solvent into a reactor. Under a nitrogen atmosphere, heat to 110 °C, continuously stir for 12 h, stop the reaction, cool to room temperature, wash with saturated ammonium chloride solution, extract with dichloromethane, dry, distill off the solvent under reduced pressure, and separate the crude product by column chromatography to obtain the target product with a yield of 82%.

[0104] The specific information of the 1H NMR spectrum of the target product in this example is as follows: 1 H NMR (600 MHz, CDCl 3 ): δ 8.26 (br s, 1H), 7.89 (d, J = 7.2 Hz, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.46 (t, J = 7.8 Hz, 2H), 7.30 (s, 1H), 7.16 (s, 1H), 7.09 (d, J = 10.3 Hz, 1H), 5.37 (s, 2H), 3.93 (s, 2H).

[0105] Example 4

[0106] This example provides a heterocyclic carboxymethyl ketone compound: 2-oxo-2-phenethyl 2-(2-methyl-1H-indol-3-yl)acetate, and the specific structure is as follows:

[0107]

[0108] This example provides a preparation method of 2-oxo-2-phenethyl 2-(2-methyl-1H-indol-3-yl)acetate, including:

[0109] Add 0.1 mmol of 2-methyl-3-indoleacetic acid, 0.20 mmol of benzoyl sulfonium ylide, 0.002 mmol of dichloro(1,5-cyclooctadiene)iridium(III) dimer, 0.004 mmol of 1,10-phenanthroline, and 0.5 mL of DMF solvent into a reactor. Under a nitrogen atmosphere, heat to 110 °C, stir continuously for 16 h, stop the reaction, cool to room temperature, wash with saturated ammonium chloride solution, extract with dichloromethane, dry, remove the solvent by vacuum distillation, and separate the crude product by column chromatography to obtain the target product with a yield of 61%.

[0110] The nuclear magnetic resonance hydrogen spectrum information of the target product in this example is specifically as follows: 1 H NMR(600MHz,CDCl 3 ):δ7.93(br s,1H),7.85(d,J=7.2Hz,2H),7.57(t,J=7.4Hz,2H),7.48–7.40(m,2H),7.29–7.21(m,1H),7.15–7.07(m,2H),5.29(s,2H),3.87(s,2H),2.39(s,3H).

[0111] Example 5

[0112] This example provides a heterocyclic carboxymethyl ketone compound: 2-oxo-2-phenethyl 3-(1H-indol-3-yl)propionate, and the specific structure is as follows:

[0113]

[0114] This example provides a preparation method of 2-oxo-2-phenethyl 3-(1H-indol-3-yl)propionate, including:

[0115] Add 0.1 mmol of 3-indolepropionic acid, 0.20 mmol of benzoyl sulfonium ylide, 0.004 mmol of methoxy(cyclooctadiene)iridium(III) dimer, 0.008 mmol of 1,10-phenanthroline, and 0.5 mL of DMF solvent into a reactor. Under a nitrogen atmosphere, heat to 110 °C, stir continuously for 16 h, stop the reaction, cool to room temperature, wash with saturated ammonium chloride solution, extract with dichloromethane, dry, remove the solvent by vacuum distillation, and separate the crude product by column chromatography to obtain the target product with a yield of 70%.

[0116] The nuclear magnetic resonance hydrogen spectrum information of the target product in this example is specifically as follows: 1 H NMR(600MHz,CDCl 3 ):δ8.07(br s,1H),7.91(d,J=7.2Hz,2H),7.67–7.57(m,2H),7.48(t,J=7.8Hz,2H),7.35(d,J=8.1Hz,1H),7.20(t,J=7.1Hz,1H),7.13(t,J=7.0Hz,1H),7.05(s,1H),5.35(s,2H),3.19(t,J=7.7Hz,2H),2.97–2.87(m,2H).

[0117] Example 6

[0118] This example provides a heterocyclic carboxymethyl ketone compound: 2-oxo-2-phenethyl 4-(1H-indol-3-yl)butyrate, and the specific structure is as follows:

[0119]

[0120] This example provides a preparation method of 2-oxo-2-phenethyl 4-(1H-indol-3-yl)butyrate, including:

[0121] Add 0.1 mmol of 3-indolebutyric acid, 0.20 mmol of benzoyl sulfonium ylide, 0.004 mmol of dichloroiridium(III) dimer of 1,5-cyclooctadiene, 0.008 mmol of 1,10-phenanthroline, and 0.5 mL of dimethyl sulfoxide solvent into a reactor. Under a nitrogen atmosphere, heat to 110 °C, continuously stir for 12 h, stop the reaction, cool to room temperature, wash with saturated ammonium chloride solution, extract with dichloromethane, dry, distill off the solvent under reduced pressure, and separate the crude product by column chromatography to obtain the target product with a yield of 71%.

[0122] The nuclear magnetic resonance hydrogen spectrum information of the target product in this example is specifically as follows: 1 H NMR(600MHz,CDCl 3): δ 8.05 (br s, 1H), 7.91 (d, J = 7.2 Hz, 2H), 7.64 (d, J = 8.6 Hz, 1H), 7.61 (t, J = 7.4 Hz, 1H), 7.49 (t, J = 7.8 Hz, 2H), 7.35 (d, J = 8.1 Hz, 1H), 7.19 (t, J = 7.0 Hz, 1H), 7.12 (t, J = 7.0 Hz, 1H), 7.02 (s, 1H), 5.33 (s, 2H), 2.88 (t, J = 7.7 Hz, 2H), 2.57 (t, J = 7.4 Hz, 2H), 2.13 (p, J = 7.4 Hz, 2H).

[0123] Example 7

[0124] This example provides a heterocyclic carboxymethyl ketone compound: 2-oxo-2-phenethyl 1H-indole-3-carboxylate, and the specific structure is as follows:

[0125]

[0126] This example provides a preparation method of 2-oxo-2-phenethyl 1H-indole-3-carboxylate, including:

[0127] Add 0.1 mmol of 3-indolecarboxylic acid, 0.20 mmol of benzoyl sulfonium ylide, 0.004 mmol of dichloroiridium (I) dimer of 1,5-cyclooctadiene, 0.008 mmol of 1,10-phenanthroline, and 0.5 mL of DMF solvent into the reactor. Under a nitrogen atmosphere, heat to 110 °C, continuously stir for 12 h, stop the reaction, cool to room temperature, wash with saturated ammonium chloride solution, extract with dichloromethane, dry, and remove the solvent by distillation under reduced pressure. The crude product is separated by column chromatography to obtain the target product with a yield of 70%.

[0128] The nuclear magnetic resonance hydrogen spectrum information of the target product in this example is specifically as follows: 1 H NMR (600 MHz, DMSO-d 6 ): δ 12.04 (br s, 1H), 8.19 (d, J = 3.0 Hz, 1H), 8.04 (d, J = 8.4 Hz, 3H), 7.71 (t, J = 7.4 Hz, 1H), 7.59 (t, J = 7.8 Hz, 2H), 7.52 (d, J = 7.7 Hz, 1H), 7.26–7.18 (m, 2H), 5.68 (s, 2H).

[0129] Example 8

[0130] This example provides a heterocyclic carboxymethyl ketone compound: 2-oxo-2-phenethyl 5-hydroxynicotinate, and the specific structure is as follows:

[0131]

[0132] This example provides a preparation method of 2-oxo-2-phenethyl 5-hydroxynicotinate, including:

[0133] Add 0.1 mmol of 5-hydroxynicotinic acid, 0.20 mmol of benzoyl sulfonium ylide, 0.004 mmol of dichloro(1,5-cyclooctadiene)iridium(III) dimer, 0.008 mmol of 1,10-phenanthroline, and 0.5 mL of DMF solvent into a reactor. Under a nitrogen atmosphere, heat to 110 °C, continuously stir for 12 h, stop the reaction, cool to room temperature, wash with saturated ammonium chloride solution, extract with dichloromethane, dry, remove the solvent by rotary evaporation under reduced pressure, and separate the crude product by column chromatography to obtain the target product with a yield of 41%.

[0134] The 1H NMR information of the target product in this example is specifically as follows: 1 H NMR(600MHz,DMSO-d 6 ):δ10.51(s,1H),8.65(d,J=1.8Hz,1H),8.41(d,J=2.8Hz,1H),8.01(d,J=7.1Hz,2H),7.72(t,J=7.4Hz,1H),7.69(dd,J=2.8,1.8Hz,1H),7.59(t,J=7.8Hz,2H),5.79(s,2H).

[0135] Example 9

[0136] This example provides a heterocyclic carboxymethyl ketone compound: 2-oxo-2-phenethyl 5-aminopicolinate, and the specific structure is as follows:

[0137]

[0138] This example provides a preparation method of 2-oxo-2-phenethyl 5-aminopicolinate, including:

[0139] Add 0.1 mmol of 6-aminonicotinic acid, 0.20 mmol of benzoyl sulfonium ylide, 0.004 mmol of dichloro(1,5-cyclooctadiene)iridium(III) dimer, 0.008 mmol of 1,10-phenanthroline, and 0.5 mL of DMF solvent into a reactor. Under a nitrogen atmosphere, heat to 110 °C, continuously stir for 16 h, stop the reaction, cool to room temperature, wash with saturated ammonium chloride solution, extract with dichloromethane, dry, remove the solvent by rotary evaporation under reduced pressure, and separate the crude product by column chromatography to obtain the target product with a yield of 35%.

[0140] The 1H NMR information of the target product in this example is specifically as follows:1 H NMR (600 MHz, CDCl 3 ): δ 8.84 (s, 1H), 8.10 (d, J = 8.6 Hz, 1H), 7.96 (d, J = 8.4 Hz, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 6.50 (d, J = 8.7 Hz, 1H), 5.54 (s, 2H), 4.91 (br s, 2H).

[0141] Example 10

[0142] This example provides a heterocyclic carboxymethyl ketone compound: 2-oxo-2-phenethyl pyrimidine-5-carboxylate, and the specific structure is as follows:

[0143] This example provides a preparation method of 2-oxo-2-phenethyl pyrimidine-5-carboxylate, including:

[0144] Add 0.1 mmol of pyrimidine-5-carboxylic acid, 0.20 mmol of benzoyl sulfonium ylide, 0.004 mmol of dichlorobis(1,5-cyclooctadiene)iridium(III) dimer, 0.008 mmol of 1,10-phenanthroline, and 0.5 mL of DMF solvent into a reactor. Under a nitrogen atmosphere, heat to 110 °C, continuously stir for 12 h, stop the reaction, cool to room temperature, wash with saturated ammonium chloride solution, extract with ethyl acetate, dry, distill off the solvent under reduced pressure, and separate the crude product by column chromatography to obtain the target product with a yield of 63%.

[0145] The nuclear magnetic resonance hydrogen spectrum information of the target product in this example is specifically as follows: 1 H NMR (600 MHz, CDCl 3 ): δ 9.40 (s, 1H), 9.38 (s, 2H), 7.95 (d, J = 7.2 Hz, 2H), 7.64 (t, J = 7.5 Hz, 1H), 7.52 (t, J = 7.8 Hz, 2H), 5.65 (s, 2H).

[0146] Example 11

[0147] This example provides a 2-oxo-2-phenethyl-4-hydroxymethyl benzoate, and the specific structure is as follows:

[0148]

[0149] This example provides a preparation method of 2-oxo-2-phenethyl-4-hydroxymethyl benzoate, including:

[0150] Add 0.1 mmol of 4-hydroxymethylbenzoic acid, 0.20 mmol of benzoyl sulfonium ylide, 0.004 mmol of dichloro(1,5-cyclooctadiene)iridium(III) dimer, 0.008 mmol of 1,10-phenanthroline, and 0.5 mL of DMF solvent into a reactor. Under a nitrogen atmosphere, heat to 110 °C and continuously stir for 12 h. Stop the reaction, cool to room temperature, wash with saturated ammonium chloride solution, extract with ethyl acetate, dry, and remove the solvent by distillation under reduced pressure. The crude product is separated by column chromatography to obtain the target product with a yield of 96%.

[0151] The nuclear magnetic resonance hydrogen spectrum information of the target product in this example is specifically as follows: 1 H NMR(600MHz,CDCl 3 ):δ8.08(d,J=8.2Hz,2H),7.95(d,J=7.2Hz,2H),7.61(t,J=7.4Hz,1H),7.49(t,J=7.8Hz,2H),7.42(d,J=8.1Hz,2H),5.56(s,2H),4.74(s,2H),2.41(br s,1H).

[0152] Example 12

[0153] This example provides a carboxymethyl ketone compound: 2-oxo-2-phenethyl-4-vinyl benzoate, and the specific structure is as follows:

[0154]

[0155] This example provides a preparation method of 2-oxo-2-phenethyl-4-vinyl benzoate, including:

[0156] Add 0.1 mmol of 4-vinylbenzoic acid, 0.20 mmol of benzoyl sulfonium ylide, 0.004 mmol of dichloro(1,5-cyclooctadiene)iridium(III) dimer, 0.008 mmol of 1,10-phenanthroline, and 0.5 mL of DMF solvent into a reactor. Under a nitrogen atmosphere, heat to 110 °C and continuously stir for 12 h. Stop the reaction, cool to room temperature, wash with saturated ammonium chloride solution, extract with ethyl acetate, dry, and remove the solvent by distillation under reduced pressure. The crude product is separated by column chromatography to obtain the target product with a yield of 88%.

[0157] The nuclear magnetic resonance hydrogen spectrum information of the target product in this example is specifically as follows: 1 H NMR(600MHz,CDCl 3): δ 8.09 (d, J = 8.3 Hz, 2H), 7.96 (d, J = 7.2 Hz, 2H), 7.61 (t, J = 7.5 Hz, 1H), 7.49 (t, J = 7.8 Hz, 4H), 6.76 (dd, J = 17.6, 10.9 Hz, 1H), 5.88 (d, J = 18.2 Hz, 1H), 5.56 (s, 2H), 5.39 (d, J = 11.4 Hz, 1H).

[0158] Example 13

[0159] This example provides a carboxymethyl ketone compound: 2-oxo-2-phenethyl acetate, and the specific structure is as follows:

[0160] This example provides a preparation method of 2-oxo-2-phenethyl acetate, including:

[0161] Add 0.1 mmol of acetic acid, 0.20 mmol of benzoyl sulfonium ylide, 0.004 mmol of dichlorobis(1,5-cyclooctadiene)iridium(III) dimer, 0.008 mmol of 1,10-phenanthroline, and 0.5 mL of DMF solvent into the reactor. Under the nitrogen atmosphere, heat to 110 °C, stir continuously for 10 h, stop the reaction, cool to room temperature, wash with saturated ammonium chloride solution, extract with ethyl acetate, dry, remove the solvent by distillation under reduced pressure, and separate the crude product by column chromatography to obtain the target product with a yield of 77%.

[0162] The nuclear magnetic resonance hydrogen spectrum information of the target product in this example is specifically as follows: 1 H NMR (600 MHz, CDCl 3 ): δ 7.90 (d, J = 7.2 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.47 (t, J = 7.8 Hz, 2H), 5.33 (s, 2H), 2.22 (s, 3H).

[0163] Example 14

[0164] This example provides a heterocyclic carboxymethyl ketone compound: ethyl 2-oxo-2-(p-tolyl)-2-(1H-indol-3-yl)acetate, and the specific structure is as follows:

[0165]

[0166] This example provides a preparation method of ethyl 2-oxo-2-(p-tolyl)-2-(1H-indol-3-yl)acetate, including:

[0167] Add 0.1 mmol of 3-indoleacetic acid, 0.20 mmol of 4-methylbenzoyl sulfonium ylide, 0.004 mmol of dichlorobis(1,5-cyclooctadiene)iridium(III), 0.008 mmol of 1,10-phenanthroline, and 0.5 mL of DMF solvent into a reactor. Under a nitrogen atmosphere, heat to 110 °C and continuously stir for 12 h. Stop the reaction, cool to room temperature, wash with saturated ammonium chloride solution, extract with dichloromethane, dry, remove the solvent by distillation under reduced pressure, and separate the crude product by column chromatography to obtain the target product with a yield of 83%.

[0168] The nuclear magnetic resonance hydrogen spectrum information of the target product in this example is specifically as follows: 1 H NMR(600MHz,CDCl 3 ):δ8.23(br s,1H),7.79(d,J=8.2Hz,2H),7.66(d,J=7.9Hz,1H),7.33(d,J=7.2Hz,1H),7.25(d,J=8.1Hz,2H),7.21–7.12(m,3H),5.33(s,2H),3.96(s,2H),2.41(s,3H).

[0169] Example 15

[0170] This example provides a heterocyclic carboxymethyl ketone compound: ethyl 2-(4-fluorophenyl)-2-oxo-2-(1H-indol-3-yl)acetate, and the specific structure is as follows:

[0171]

[0172] This example provides a preparation method of ethyl 2-(4-fluorophenyl)-2-oxo-2-(1H-indol-3-yl)acetate, including:

[0173] Add 0.1 mmol of 3-indoleacetic acid, 0.20 mmol of 4-fluorobenzoyl sulfonium ylide, 0.004 mmol of dichlorobis(1,5-cyclooctadiene)iridium(III), 0.008 mmol of 1,10-phenanthroline, and 0.5 mL of DMF solvent into a reactor. Under a nitrogen atmosphere, heat to 110 °C and continuously stir for 12 h. Stop the reaction, cool to room temperature, wash with saturated ammonium chloride solution, extract with dichloromethane, dry, remove the solvent by distillation under reduced pressure, and separate the crude product by column chromatography to obtain the target product with a yield of 88%.

[0174] The nuclear magnetic resonance hydrogen spectrum information of the target product in this example is specifically as follows: 1 H NMR(600MHz,CDCl 3): δ 8.26 (br s, 1H), 7.86 (dd, J = 8.7, 5.4 Hz, 2H), 7.65 (d, J = 7.8 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.19 (t, J = 7.4 Hz, 1H), 7.15 (t, J = 7.4 Hz, 1H), 7.09 (t, J = 8.4 Hz, 3H), 5.27 (s, 2H), 3.94 (s, 2H).

[0175] Example 16

[0176] This example provides a heterocyclic carboxymethyl ketone compound: ethyl 2-(4-iodophenyl)-2-oxo-2-(1H-indol-3-yl)acetate, and the specific structure is as follows:

[0177]

[0178] This example provides a preparation method of ethyl 2-(4-iodophenyl)-2-oxo-2-(1H-indol-3-yl)acetate, including:

[0179] Add 0.1 mmol of 3-indoleacetic acid, 0.20 mmol of 4-iodobenzoyl sulfonium ylide, 0.004 mmol of dichloroiridium(III) dimer of 1,5-cyclooctadiene, 0.008 mmol of 1,10-phenanthroline, and 0.5 mL of DMF solvent into a reactor. Under a nitrogen atmosphere, heat to 110 °C, stir continuously for 12 h, stop the reaction, cool to room temperature, wash with saturated ammonium chloride solution, extract with dichloromethane, dry, remove the solvent by distillation under reduced pressure, and separate the crude product by column chromatography to obtain the target product with a yield of 60%.

[0180] The nuclear magnetic resonance hydrogen spectrum information of the target product in this example is specifically as follows: 1 H NMR (600 MHz, CDCl 3 ): δ 8.12 (br s, 1H), 7.78 (d, J = 8.5 Hz, 2H), 7.64 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 8.1 Hz, 1H), 7.23–7.19 (m, 2H), 7.14 (t, J = 7.0 Hz, 1H), 5.27 (s, 2H), 3.95 (s, 2H).

[0181] Example 17

[0182] This example provides a heterocyclic carboxymethyl ketone compound: ethyl 2-oxo-2-(thiophen-2-yl)-2-(1H-indol-3-yl)acetate, and the specific structure is as follows:

[0183]

[0184] This example provides a preparation method of ethyl 2-oxo-2-(thiophen-2-yl)-2-(1H-indol-3-yl)acetate, including:

[0185] Add 0.1 mmol of 3-indoleacetic acid, 0.20 mmol of 2-thienylmethylsulfonium ylide, 0.004 mmol of dichlorobis(1,5-cyclooctadiene)iridium(III), 0.008 mmol of 1,10-phenanthroline, and 0.5 mL of DMF solvent into a reactor. Under a nitrogen atmosphere, heat to 110 °C, stir continuously for 12 h, stop the reaction, cool to room temperature, wash with saturated ammonium chloride solution, extract with dichloromethane, dry, remove the solvent by distillation under reduced pressure, and separate the crude product by column chromatography to obtain the target product with a yield of 72%.

[0186] The nuclear magnetic resonance hydrogen spectrum information of the target product in this example is specifically as follows: 1 H NMR(600MHz,CDCl 3 ):δ8.25(br s,1H),7.68–7.62(m,3H),7.32(d,J=8.1Hz,1H),7.19(t,J=7.0Hz,1H),7.17–7.11(m,2H),7.09(dd,J=4.9,3.9Hz,1H),5.22(s,2H),3.95(s,2H). Example 18

[0187] This example provides a heterocyclic carboxymethyl ketone compound: 2-cyclohexyl-2-oxoethyl 2-(1H-indol-3-yl)acetate, and the specific structure is as follows:

[0188]

[0189] This example provides a preparation method of 2-cyclohexyl-2-oxoethyl 2-(1H-indol-3-yl)acetate, including:

[0190] Add 0.1 mmol of 3-indoleacetic acid, 0.20 mmol of cyclohexylmethylsulfonium ylide, 0.004 mmol of dichlorobis(1,5-cyclooctadiene)iridium(III), 0.008 mmol of 1,10-phenanthroline, and 0.5 mL of DMF solvent into a reactor. Under a nitrogen atmosphere, heat to 110 °C, stir continuously for 12 h, stop the reaction, cool to room temperature, wash with saturated ammonium chloride solution, extract with dichloromethane, dry, remove the solvent by distillation under reduced pressure, and separate the crude product by column chromatography to obtain the target product with a yield of 75%.

[0191] The nuclear magnetic resonance hydrogen spectrum information of the target product in this example is specifically as follows: 11H NMR (600 MHz, CDCl 3 ): δ 8.31 (br s, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.19 (t, J = 8.1 Hz, 1H), 7.14 (t, J = 8.0 Hz, 1H), 7.07 (s, 1H), 4.75 (s, 2H), 3.89 (s, 2H), 2.39–2.34 (m, 1H), 1.83–1.72 (m, 4H), 1.65–1.63 (m, 1H), 1.40–1.33 (m, 2H), 1.25–1.15 (m, 3H).

[0192] Example 19

[0193] This example provides a heterocyclic carboxymethyl ketone compound: 3-cyclohexyl-2-oxopropyl 2-(1H-indol-3-yl)acetate, and the specific structure is as follows:

[0194]

[0195] This example provides a preparation method of 3-cyclohexyl-2-oxopropyl 2-(1H-indol-3-yl)acetate, including:

[0196] Add 0.1 mmol of 3-indoleacetic acid, 0.20 mmol of cyclohexylacetylsulfonium ylide, 0.004 mmol of dichloroiridium(III) dimer of 1,5-cyclooctadiene, 0.008 mmol of 1,10-phenanthroline, and 0.5 mL of DMF solvent into a reactor. Under a nitrogen atmosphere, heat to 110 °C, stir continuously for 12 h, stop the reaction, cool to room temperature, wash with saturated ammonium chloride solution, extract with dichloromethane, dry, remove the solvent by distillation under reduced pressure, and separate the crude product by column chromatography to obtain the target product with a yield of 96%.

[0197] The nuclear magnetic resonance hydrogen spectrum information of the target product in this example is specifically as follows: 1 1H NMR (600 MHz, CDCl 3 ): δ 8.31 (br s, 1H), 7.63 (d, J = 8.9 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.20 (t, J = 8.1 Hz, 1H), 7.15 (t, J = 8.0 Hz, 1H), 7.06 (s, 1H), 4.64 (s, 2H), 3.90 (s, 2H), 2.21 (d, J = 6.9 Hz, 2H), 1.86–1.78 (m, 1H), 1.67–1.64 (m, 5H), 1.29–1.20 (m, 2H), 1.16–1.08 (m, 1H), 0.91–0.83 (m, 2H).

[0198] The technical features of the above embodiments can be combined arbitrarily. For the sake of concise description, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, it should be considered as the scope described in this specification.

[0199] The above embodiments only represent several implementation manners of the present application, and their descriptions are relatively specific and detailed, but they should not be construed as limiting the scope of the invention patent. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present application, several deformations and improvements can still be made, and these all belong to the protection scope of the present application. Therefore, the protection scope of the patent of the present application shall be subject to the appended claims.

Claims

1. A method for preparing a carboxymethyl ketone compound, characterized in that, it includes: in the presence of an iridium catalyst, dissolving a carboxylic acid compound, a sulfonium ylide compound and a ligand in a solvent and reacting them to prepare the carboxymethyl ketone compound; the structure of the carboxylic acid compound is shown as follows: the structure of the sulfonium ylide compound is shown as follows: the structure of the carboxymethyl ketone compound is shown as follows: Among them, R 1 is selected from any one of the following groups: aryl, alkyl, heterocyclic group, heterocyclic group linked with any one of alkyl, halogen, alkenyl, hydroxyl and amino; among them, the heterocyclic group is selected from any one of heteroalkyl and heteroaryl, the heteroalkyl refers to that at least one carbon atom in the cycloalkyl is replaced by a non-carbon atom, and the non-carbon atom is an N atom, an O atom or an S atom, the heteroalkyl is a saturated ring or a partially unsaturated ring, and the heteroaryl is that at least one carbon atom in the aryl is replaced by an N atom R 2 Selected from any one of aryl, alkyl, and heterocyclic group; the aryl group is selected from any one of benzene, biphenyl, naphthalene, anthracene, phenanthrene, picene and triphenylene; the iridium catalyst is selected from at least one of 1,5-cyclooctadiene iridium dichloride dimer, methoxy(cyclooctadiene)iridium dimer, dichloro(cyclooctene)iridium(I) dimer and dichloro(pentamethylcyclopentadienyl)iridium(III) dimer; the ligand is selected from at least one of triphenylphosphine, N,N,N',N'-tetramethylethylenediamine, 2,2'-bipyridine and 1,10-phenanthroline; the solvent is selected from at least one of 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide and dimethyl sulfoxide.

2. A method for preparing a carboxymethyl ketone compound, characterized in that, it includes: in the presence of an iridium catalyst, dissolving a carboxylic acid compound, a sulfonium ylide compound and a ligand in a solvent and reacting them to prepare the carboxymethyl ketone compound; the structure of the carboxylic acid compound is shown as follows: the structure of the sulfonium ylide compound is shown as follows: the structure of the carboxymethyl ketone compound is shown as follows: Among them, R 1 is selected from any one of the following groups: aryl, alkyl, heterocyclic group, heterocyclic group connected with any one of alkyl, halogen, alkenyl, hydroxyl and amino; among them, the heterocyclic group is selected from any one of heteroalkyl and heteroaryl, the heteroalkyl refers to at least one carbon atom in the cycloalkyl group is replaced by a non-carbon atom, the non-carbon atom is N atom, O atom, S atom, the heteroalkyl is a saturated ring or a partially unsaturated ring, and the heteroaryl is a group in which at least one carbon atom in the aryl group is replaced by an N atom, the aryl group is selected from any one of benzene, biphenyl, naphthalene, anthracene, phenanthrene, picene and triphenylene; and the sulfonium ylide compound is selected from at least one of benzoyl sulfonium ylide, 4-methylbenzoyl sulfonium ylide, 4-fluorobenzoyl sulfonium ylide, 4-iodobenzoyl sulfonium ylide, 2-thiophenecarbonyl sulfonium ylide and cyclohexylcarbonyl sulfonium ylide; the iridium catalyst is selected from at least one of 1,5-cyclooctadiene iridium dichloride dimer, methoxy(cyclooctadiene)iridium dimer, dichloro(cyclooctene)iridium(I) dimer and dichloro(pentamethylcyclopentadienyl)iridium(III) dimer; the ligand is selected from at least one of triphenylphosphine, N,N,N',N'-tetramethylethylenediamine, 2,2'-bipyridine and 1,10-phenanthroline; the solvent is selected from at least one of 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide and dimethyl sulfoxide.

3. A method for preparing a carboxymethyl ketone compound, characterized in that, it includes: in the presence of an iridium catalyst, dissolving a carboxylic acid compound, a sulfonium ylide compound and a ligand in a solvent and reacting them to prepare the carboxymethyl ketone compound; the structure of the carboxylic acid compound is shown as follows: and the carboxylic acid compound is selected from at least one of 3-indoleacetic acid, 5-fluoro-3-indoleacetic acid, 6-chloro-3-indoleacetic acid, 2-methyl-3-indoleacetic acid, 3-indolepropionic acid, 3-indolebutyric acid, 3-indolecarboxylic acid, 5-hydroxynicotinic acid, 6-aminonicotinic acid, pyrimidine-5-carboxylic acid, 4-hydroxymethylbenzoic acid and 4-vinylbenzoic acid; the structure of the sulfonium ylide compound is shown as follows: The structure of the carboxymethyl ketone compound is as follows: R 2 Selected from any one of aryl, alkyl and heterocyclic group; Wherein, the aryl group is selected from any one of benzene, biphenyl, naphthalene, anthracene, phenanthrene, pyrene and triphenylene; The iridium catalyst is selected from at least one of 1,5-cyclooctadiene iridium dichloride dimer, methoxy(cyclooctadiene)iridium dimer, chloro bis(cyclooctene)iridium(I)dimer and dichloro(pentamethylcyclopentadienyl)iridium(III)dimer; The ligand is selected from at least one of triphenylphosphine, N,N,N',N'-tetramethylethylenediamine, 2,2'-bipyridine and 1,10-phenanthroline; The solvent is selected from at least one of 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide and dimethyl sulfoxide.

4. The preparation method according to claim 1, characterized in that the molar ratio of the iridium catalyst, ligand, carboxylic acid compound and sulfur ylide is (0.01-0.05):(0.02-0.10):1:(1.0-2.0).

5. The preparation method according to any one of claims 1-4, characterized in that the preparation method satisfies at least one of the following characteristics: (1) The reaction is carried out in an inert gas; (2) The reaction is carried out at 90°C to 120°C for 8 to 16 h; (3) After the reaction is completed, a purification step is further included, including: after cooling the reaction mixture, washing and extracting the mixture to obtain the carboxymethyl ketone compound.

6. The preparation method according to claim 5, characterized in that the inert gas is nitrogen or argon.

7. The preparation method according to claim 5, characterized in that the reaction is carried out at 100°C to 120°C for 8 to 12 h.

8. The preparation method according to claim 5, characterized in that washing with saturated ammonium chloride solution.

9. The preparation method according to claim 5, characterized in that the extraction solvent used for extraction is selected from at least one of ethyl acetate and dichloromethane.

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