Application of oxyalkyl isourea in introduction of methyl and isotope labeling of methyl

Abstract

The invention discloses application of oxyalkyl isourea in introduction of methyl and isotope labeling of methyl. The oxygen alkyl isourea comprises two applications: 1, nucleophilic substitution reaction: heating and stirring oxygen alkyl isourea and a nucleophilic reagent under the condition of not adding any exogenous alkali at 50-130 DEG C to react, so as to obtain a methylated or isotope labeled methylated product; and 2, Suzuki-Miyaura coupling reaction: carrying out stirring reaction on oxygen alkyl isourea and aryl boride under the action of a palladium catalyst and alkali at 60-130 DEG C to obtain a methylated or isotope labeled methylated product. The methyl of the oxygen alkyl isourea is derived from a cheap methanol compound, the limitation that exogenous alkali must be used in an existing alkylation reagent is overcome through the nucleophilic substitution reaction, methyl and isotope labeling methyl can be efficiently introduced into medicine molecules, construction of C-O, C-S, C-N and C-C four types of chemical bonds is achieved, and large-scale and industrial application is easy.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to the application of oxoalkylisoureas in the introduction of methyl groups and isotopically labeled methyl groups. More particularly, it relates to a method for efficiently introducing methyl groups, deuterated methyl groups, etc., into organic compounds via nucleophilic substitution reactions under exogenous base-free conditions and via Suzuki-Miyaura coupling reactions catalyzed by palladium, using oxoalkylisoureas. 13 C-labeled methyl and 13 A method for labeling deuterated methyl groups with C. Background Technology

[0002] Introducing methyl groups into drug molecules can generate favorable desolvation energy effects, regulate metabolic stability, precisely control hydrophobic interactions, and induce conformational changes, thereby significantly enhancing drug activity and solubility. This "magical methyl effect" has attracted widespread attention in the field of medicinal chemistry. Building upon this, replacing the hydrogen atoms in the methyl group with stable isotopes (deuterium or...) 13 (C) It can also be used as a non-radioactive tracer to study the metabolic processes of drug molecules, achieving higher labeling depth and exploring multiple metabolic pathways simultaneously, maximizing the amount of information obtained in a single experiment. For example, Austedo (deuterated benzodiazepine), a drug for treating Huntington's disease, and glipizide, a hypoglycemic drug, utilize the kinetic isotope effect produced by replacing hydrogen atoms with deuterium atoms to effectively reduce their metabolic degradation rate, thereby achieving a dose advantage; 13 C-labeled riboflavin and 13 C / deuterium dual-labeled apixaban is widely used in metabolic studies and quantitative analysis. Therefore, developing efficient and mild methods to introduce stable isotope-labeled methyl groups into drug molecules has significant scientific and practical value.

[0003] Currently, methods for introducing methyl groups and isotopically labeled methyl groups into organic molecules mainly include hydrogen / deuterium exchange and direct methylation using isotopically labeled methylating agents. CD3I, CD3OD, and (CD3)2SO4 are the most commonly used deuterated methyl sources in synthetic chemistry, but they suffer from problems such as volatility, corrosiveness, toxicity, and carcinogenicity. To address these issues, researchers have developed various novel methylating agents in recent years, but existing technologies still have their limitations.

[0004] CN117946067B discloses a method for achieving deuteromethylation of nucleophiles, which uses a thiaanthraium salt-based deuteromethylating agent (5-deuteromethyl-5H-thiophene-5-onium trifluoromethanesulfonate) to react with the nucleophile under alkaline conditions to achieve deuteromethylation. While this technique can achieve deuteromethylation of nucleophiles, it has the following problems: First, the reaction requires the addition of an exogenous base (such as triethylamine), making it unsuitable for acid- and base-sensitive substrates, and the added base may trigger side reactions; second, the synthesis of the thiaanthraium salt reagent is complex, requiring multiple reaction steps, resulting in high costs; third, this reagent is only applicable to the introduction of deuteromethyl groups and does not address... 13 Fourth, this reagent can only construct CS, CN, and CO bonds, and cannot be used to construct CC bonds. It is worth noting that all nucleophilic substitution methylation reactions in the prior art rely on the participation of an exogenous base. Without an exogenous base, it is difficult to obtain the corresponding methylated products when reacting with carboxylic acids, phenols, thiols, sulfonamides, and sulfonic acids.

[0005] CN120923407A discloses a method for synthesizing oxoalkylisoureas and their application as a radical alkylating agent. This method uses alcohols and carbodiimides as raw materials to synthesize oxoalkylisoureas under metal catalysis, and then applies them as a radical alkylating agent in a nickel-catalyzed coupling reaction, achieving the preparation of the alkylated product through a single-electron transfer mechanism. However, this method has the following problems: First, oxoalkylisoureas only participate in the reaction as radical precursors, and their reaction mechanism is radical cross-coupling, not an electrophilic two-electron nucleophilic substitution reaction; second, this method does not address the application of oxoalkylisoureas in nucleophilic substitution reactions, nor does it address the introduction of methyl groups or isotopically labeled methyl groups; third, the nickel-catalyzed system used in this method requires the addition of ligands and bases, making the reaction conditions relatively complex.

[0006] In summary, existing methylating reagents all rely on the participation of an exogenous base when used in nucleophilic substitution reactions. A long-standing technical bias in this field holds that oxoalkylisoureas require the addition of an exogenous base to achieve methylation in nucleophilic substitution reactions. Therefore, there is an urgent need to develop a method for methylation of methyl groups and isotopically labeled methyl groups without the need for an exogenous base. This method should possess high reactivity, excellent functional group compatibility and chemoselectivity, and be capable of constructing four types of chemical bonds: CO, CS, CN, and CC. Summary of the Invention

[0007] The purpose of this invention is to provide an application of oxyalkylisourea in the introduction of methyl groups and isotopically labeled methyl groups, through two different reaction mechanisms, to efficiently achieve the conversion of methyl, deuterated methyl, and... 13 C-labeled methyl and 13The introduction of C-labeled deuterated methyl groups. This method exhibits excellent functional group compatibility and chemoselectivity, mild reaction conditions, simple operation, low cost, and no special equipment requirements. It overcomes the technical bias of existing technologies that require the use of exogenous bases and has promising application prospects.

[0008] To achieve the above objectives, the present invention provides the following technical solution:

[0009] In a first aspect, the present invention provides the application of oxoalkylisourea in nucleophilic substitution reactions to introduce methyl groups or isotopically labeled methyl groups, wherein the structure of the oxoalkylisourea is shown in Formula I:

[0010]

[0011] Among them, R 1 Represents CH3, CD3, 13 CH3 13 Any one of CD3; R 2 and R 3 Each of these compounds independently represents any one of ethyl, propyl, n-butyl, n-pentyl, benzyl, isopropyl, cyclohexyl, tert-butyl, p-tolyl, 3-dimethylaminopropyl, 2,6-diisopropylphenyl, and trimethylsilyl. The specific application method is as follows: the oxyalkylisourea shown in Formula I and the nucleophile shown in Formula II are added to organic solvent A. Under inert gas protection and without the addition of any exogenous base, the reaction is carried out at 50–130°C with stirring. After the reaction is complete, the mixture is separated and purified to obtain the methylated or isotopically labeled methylated product shown in Formula III.

[0012]

[0013] The nucleophiles mentioned above are selected from any one of carboxylic acid compounds, sulfonic acid compounds, phosphoric acid compounds, phenolic compounds, thiol compounds, and amine compounds.

[0014] Furthermore, the aforementioned carboxylic acid compounds are selected from any one of L-methionine, L-cysteine, L-aspartic acid, L-tryptophan, N-tert-butoxycarbonyl-L-tryptophan, L-phenylalanine, D-homophenylalanine, L-glutamine, (1S)-(-)-camphoric acid, ursolic acid, lithocholic acid, naproxen, indomethacin, isocolic acid, clofibrate, bezafibrate, and febuxostat; or the carboxylic acid compounds are selected from those with the structural formula R. 4 Compounds with -COOH, where R 4 It is phenyl, or R 4 It is a phenyl group that is substituted with any one or more of the following: C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, halogen, cyano, nitro, and amino.

[0015] Furthermore, the structural formula of the above-mentioned sulfonic acid compounds is R5 -SO3H, where R 5 It is selected from any one of phenyl, C1-C6 alkyl-substituted phenyl, naphthyl, C1-C6 alkyl-substituted naphthyl, and 5-dimethylamino-1-naphthyl.

[0016] Furthermore, the structural formula of the above-mentioned phosphate compounds is (R 6 O)2-P(O)-OH, where R 6 It is selected from any one of phenyl and C1-C4 alkyl-substituted phenyl.

[0017] Furthermore, the aforementioned phenolic compounds are selected from any one of estrone, coumarin, maltol, vanillin, benzo[a]chromone, benzbromarone, and phenolphthalein; or the phenolic compounds are selected from those with the structural formula R. 7 Compounds with -OH groups, where R 7 It is phenyl, or R 7 It is a phenyl group that is substituted with any one or more of the following: C1-C6 alkyl, C1-C6 alkoxy, amino, cyano, halogen, aldehyde, and benzoyl.

[0018] Furthermore, the aforementioned thiol compound is selected from any one of 1-thio-BD-glucosetetraacetate, methimazole, penicillamine, and captopril; or the thiol compound is selected from the compound with the structural formula R. 8 -SH compounds, where R 8 C3-C8 substituted with alkyl, phenyl, or hydroxyl groups 10 Any one of the alkyl groups, or R 8 It is a phenyl group that is substituted with any one or more of the following: C1 to C6 alkyl, amino, acetamino, hydroxyl, halogen, cyano, and nitro.

[0019] Furthermore, the aforementioned amine compound is selected from any one of sulfamethoxazole, celecoxib, sulfadiazine, dimethylpyrimidine, phthalimide, saccharin, glibenclamide, and pioglitazone; or the amine compound is selected from the compound with the structural formula […]. The compound in which R 10 It is any one of phenyl, thiophene, or halothiophene, or R 10 It is a phenyl group that is substituted with any one or more of the following: C1-C6 alkyl, C1-C6 alkoxy, amino, acetamino, hydroxyl, halogen, cyano, and nitro.

[0020] Furthermore, in the application of the above-mentioned oxoalkylisourea to introduce methyl or isotopically labeled methyl in nucleophilic substitution reactions, the amount of the oxoalkylisourea is preferably 2.0 to 3.0 times the molar amount of the nucleophile.

[0021] Furthermore, in the application of the above-mentioned oxoalkyl isourea to introduce methyl groups or isotopically labeled methyl groups in nucleophilic substitution reactions, the organic solvent A is preferably selected from any one of N,N-dimethylacetamide, N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylpropenylurea, tetrahydrofuran, 1,4-dioxane, 1,3-dioxolane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, acetonitrile, toluene, methyl tert-butyl ether, cyclopentyl methyl ether, dichloromethane, dichloroethane, diethyl ether, ethyl acetate, and dimethyl sulfoxide.

[0022] Secondly, this invention provides an application of the above-mentioned oxyalkylisourea in the Suzuki-Miyaura coupling reaction to introduce methyl groups or isotopically labeled methyl groups. The specific application method is as follows: the oxyalkylisourea shown in Formula I, along with an arylboride, a palladium catalyst, and a base, are added to an organic solvent. The reaction is carried out under inert gas protection with stirring at 60–130°C. After the reaction is completed, the mixture is separated and purified to obtain the methylated or isotopically labeled methylated product. The arylboride is selected from any one of arylboronic acid, pinacol arylboronic acid, neopentyl glycol arylboronic acid, and potassium aryltrifluoroborate.

[0023] Furthermore, the aryl group in the above-mentioned arylborides is selected from phenyl, substituted phenyl, naphthyl, substituted naphthyl, anthracene, substituted anthracene, pyrene, substituted pyrene, biphenyl, substituted biphenyl, carbazolyl, substituted carbazolyl, indolyl, substituted indolyl, quinolinyl, substituted quinolinyl, quinoxalinyl, substituted quinoxalinyl, benzoxadiazolyl, substituted benzoxadiazolyl, pyridinyl, substituted pyridinyl; the substitution refers to being replaced by one or more groups selected from C1-C4 alkyl, C1-C4 alkoxy, hydroxymethyl, halogen, cyano, nitro, amino, acetamino, acetoxy, benzoyl, methanesulfonamide, halogen. The phenyl group is substituted; or the arylboride is selected from any one of 6-(4-BOC-1-piperazino)pyridine-3-boronic acid pinacol ester, N,N-dipropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl)benzenesulfonamide, isopropyl 2-methyl-2-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl)benzoyl)phenoxy)propionate or ethyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl)phenoxy)propionate.

[0024] Furthermore, in the application of the above-mentioned oxyalkylisourea to introduce methyl groups or isotopically labeled methyl groups in the Suzuki-Miyaura coupling reaction, the palladium catalyst is selected from palladium chloride, palladium bromide, palladium iodide, palladium acetate, dichloro[2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]palladium(II), 1,1'-bis(diphenylphosphino)ferrocene palladium dibromide(II), dichloro(N,N,N',N'-tetramethylethylenediamine)palladium(II), bis(triphenylphosphine)palladium(O), bis(tri-tert-butylphosphine)palladium(O), and (R)-1-[(SP)-2-(dicyclohexylphosphino)ferrocene]ethyldi-tert-butylphosphine. Palladium dichloride (II), bis(tri-tert-butylphosphine)palladium (0), methanesulfonic acid (2-di-tert-butylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium (II), 1,1'-bis(diisopropylphosphine)ferrocene palladium dichloride, dichlorobis(tricyclohexylphosphine)palladium, dichloro(1,1-bis(diphenylphosphine)ferrocene)palladium (II) acetone adduct, bis(tricyclohexylphosphine)palladium dichloride, tetra(triphenylphosphine)palladium, 1,1'-bis(di-cyclohexylphosphine)ferrocene palladium dichloride, tri(dibenzylideneacetone)palladium (0)

[0025] Furthermore, in the application of the above-mentioned oxyalkylisourea to introduce methyl or isotopically labeled methyl groups in the Suzuki-Miyaura coupling reaction, the base is selected from any one of diisopropylamine, N,N-diisopropylethylamine, triethylamine, tripropylamine, tributylamine, N,N-diethylcyclohexylamine, dicyclohexylamine, N-methyldicyclohexylamine, cesium acetate, sodium acetate, magnesium acetate, sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate.

[0026] Furthermore, in the application of the above-mentioned oxyalkylisourea to introduce methyl or isotopically labeled methyl in the Suzuki-Miyaura coupling reaction, the amount of the oxyalkylisourea is preferably 1.0 to 5.0 times the molar amount of the arylboride; the amount of the palladium catalyst is preferably 2% to 20% of the molar amount of the arylboride; and the amount of the base is preferably 0.5 to 5.0 times the molar amount of the arylboride.

[0027] Furthermore, in the application of the above-mentioned oxyalkylisourea to introduce methyl or isotopically labeled methyl groups in the Suzuki-Miyaura coupling reaction, the organic solvent B is selected from any one of N,N-dimethylacetamide, N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylpropenylurea, 1,3-dimethyl-2-imidazolinone, tetrahydrofuran, 1,4-dioxane, 1,3-dioxolane, acetonitrile, toluene, methyl tert-butyl ether, cyclopentyl methyl ether, dichloromethane, dichloroethane, diethyl ether, ethyl acetate, and dimethyl sulfoxide.

[0028] The preparation method of the oxoalkyl isourea of ​​the present invention is as follows: under cobalt chloride catalysis, methanol or its isotope-labeled product is reacted with carbodiimide at 60°C under inert gas protection. o The reaction was stirred at step C, and after completion, the product was separated and purified to obtain oxyalkylisourea. The amount of cobalt chloride used was 0.005 times the molar amount of methanol or its isotope-labeled product, and the amount of carbodiimide used was 1.0 times the molar amount of methanol or its isotope-labeled product. For specific preparation methods, refer to CN120923407A.

[0029] The beneficial effects of this invention are as follows:

[0030] 1. This invention is the first to discover that oxyalkylisoureas can efficiently complete nucleophilic methylation reactions under heating conditions without exogenous base, avoiding side reactions that may be caused by the addition of an external base. This method is particularly suitable for the later-stage modification of acid- and base-sensitive substrates. This method does not require a metal catalyst, conforms to the principles of green chemistry, and has successfully achieved methylation and isotope-labeled methylation modifications of various drug molecules, including febuxostat, benzbromarone, celecoxib, and indomethacin, with yields reaching up to 99%.

[0031] 2. This invention utilizes inexpensive and readily available methanol and its isotope markers (CD3OD, ... 13 CH3OH, 13 Using CD3OD as a methyl source, an oxoalkylisourea reagent is synthesized in one step, which can systematically introduce CH3, CD3, ... 13 CH3 13 Based on the four forms of methyl groups in CD3 and isotopically labeled methyl groups, this invention achieves efficient construction of four types of chemical bonds: CO, CS, CN, and CC, through two reaction modes: the nucleophilic substitution reaction mode is applicable to a variety of nucleophilic substrates such as carboxylic acids, sulfonic acids, phosphoric acids, phenols, thiols, and amines, and can construct CO, CS, and CN bonds; the Suzuki-Miyaura coupling reaction mode is applicable to a variety of arylborides such as arylboronic acids and arylboronic esters, and can construct CC bonds.

[0032] 3. The method of this invention exhibits good tolerance to various functional groups and is suitable for the late-stage modification of complex drug molecules. The nucleophilic substitution reaction requires no exogenous base or metal catalyst, and can be carried out with only heating; the Suzuki-Miyaura coupling reaction uses a conventional palladium catalytic system with mild reaction conditions. The entire method is simple to operate, requires no special equipment, significantly reduces the preparation cost of isotope-labeled methylation reagents, provides diverse tools for drug metabolism research, and is easy to scale up and industrialize. Detailed Implementation

[0033] The present invention will be further described in detail below with reference to the embodiments, but the scope of protection of the present invention is not limited to these embodiments.

[0034] Example 1

[0035] Under an argon atmosphere, 158.1 mg (1.0 mmol) of oxyalkylisourea (Formula I-1), 165.2 mg (0.5 mmol) of febuxostat (Formula II-1), and 0.5 mL of 1,4-dioxane were sequentially added to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction tube was sealed, and the mixture was stirred at 70 °C for 12 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using petroleum ether and ethyl acetate in a volume ratio of 2:1 to obtain a white solid product of Formula III-1 in 91% yield.

[0036]

[0037] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ = 8.07 (d, J = 2.3Hz, 1H), 7.99 (dd, J = 8.8, 2.3 Hz, 1H), 6.96 (d, J = 8.9 Hz, 1H), 3.85 (d, J = 6.7 Hz, 5H), 2.69 (s, 3H), 2.15 (m 1H), 1.05 (d, J = 6.7 Hz, 6H); 13 C NMR (100 MHz, CDCl3) δ = 167.2, 162.5, 162.4, 161.3, 132.5, 131.9, 125.9, 121.4,115.4, 112.6, 102.8, 75.7, 52.2, 28.2, 19.0, 17.4; HRMS (APCI) m / z C 17 H 19 N2O3S + [M+H] + Theoretical value: 331.1111, measured value: 331.1115.

[0038] Example 2

[0039] Under an argon atmosphere, 158.1 mg (1.0 mmol) of alkylisourea (Formula I-1), 219.1 mg (0.5 mmol) of benzbromarone (Formula II-2), and 0.5 mL of 1,4-dioxane were sequentially added to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction tube was sealed, and the reaction was stirred at 110 °C for 12 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using petroleum ether and ethyl acetate in a volume ratio of 20:1 to obtain the yellow liquid product (Formula III-2) in 98% yield.

[0040]

[0041] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ = 7.99 (s, 2H),7.49 (d, J = 8.2, Hz, 1H), 7.42 (d, J = 7.7 Hz, 1H), 7.30 (d, J = 7.3 Hz, 1H), 7.24 (d, J = 7.5 Hz, 1H), 3.97 (s, 3H), 2.90 (q, J = 7.5 Hz, 2H), 1.36(t, J = 7.5 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ = 188.0, 166.9, 157.7, 153.7,137.2, 133.7, 126.4, 124.8, 123.9, 121.1, 118.5, 115.4, 111.2, 60.9, 22.1,12.3; HRMS (APCI) m / z C 18 H 15 Br2O3 + [M+H] + Theoretical value: 436.9382, measured value: 436.9388.

[0042] Example 3

[0043] Under an argon atmosphere, 158.1 mg (1.0 mmol) of oxyalkylisourea (Formula I-1), 189.2 mg (0.5 mmol) of 1-thio-BD-glucosetetraacetate (Formula II-3), and 0.5 mL of 1,4-dioxane were sequentially added to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction tube was sealed, and the mixture was stirred at 50 °C for 12 hours. After the reaction was complete, the reaction solution was extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using petroleum ether and ethyl acetate in a volume ratio of 10:1 to obtain a white solid product (Formula III-3) in 87% yield.

[0044]

[0045] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ = 5.16 (t, J = 9.4Hz, 1H), 5.07-4.98 (m, 2H), 4.34 (d, J = 10.0 Hz, 1H), 4.18 (dd, J = 12.4, 4.8 Hz, 1H), 4.07 (dd, J = 12.4, 2.3 Hz, 1H), 3.68 (m, J = 10.1, 4.8, 2.4 Hz,1H), 2.10 (s, 3H), 2.01 (s, 3H), 1.99 (s, 3H), 1.96 (s, 3H), 1.94 (s, 3H); 13 CNMR (100 MHz, CDCl3) δ = 170.6, 170.1, 169.4, 169.4, 82.8, 75.9, 73.8, 69.0,68.3, 62.1, 20.7, 20.7, 20.6, 20.6, 11.2; HRMS (APCI) m / z C 15 H 29 O9S + [M+H] + Theoretical value: 379.1057, measured value: 379.1060.

[0046] Example 4

[0047] Under an argon atmosphere, 158.1 mg (1.0 mmol) of oxyalkylisourea (Formula I-1), 132.1 mg (0.5 mmol) of diphenyl phosphate (Formula II-4), and 0.5 mL of 1,4-dioxane were sequentially added to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction tube was sealed, and the mixture was stirred at 70 °C for 12 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using petroleum ether and ethyl acetate in a 1:1 volume ratio to obtain a white solid product (Formula III-4) in 82% yield.

[0048]

[0049] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ = 7.33 (dd, J =8.7, 7.2 Hz, 4H), 7.26-7.14 (m, 6H), 3.93 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ= 150.5, 129.8, 125.4, 120.0, 55.5; 31 P NMR (162 MHz, CDCl3) δ = -10.77; HRMS(APCI) m / z C 13 H 14 O4P + [M+H] + Theoretical value: 265.0624, measured value: 265.0628.

[0050] Example 5

[0051] Under an argon atmosphere, 158.1 mg (1.0 mmol) of oxyalkylisourea (Formula I-1), 133.7 mg (0.5 mmol) of sulfamethoxazole (Formula II-5), and 0.5 mL of 1,4-dioxane were sequentially added to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction tube was sealed, and the reaction was stirred at 70 °C for 12 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using petroleum ether and ethyl acetate in a 1:1 volume ratio to obtain the white solid product of Formula III-5 in 92% yield.

[0052]

[0053] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows:1 H NMR (400 MHz, CDCl3) δ = 7.44 (d, J = 8.7Hz, 2H), 6.57 (d, J = 8.7 Hz, 2H), 6.45 (s, 1H), 4.30 (brs, 2H), 3.19 (s,3H), 2.34 (d, J = 0.9 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ = 170.2, 161.1,151.6, 129.4, 124.3, 114.0, 97.6, 35.0, 12.7; HRMS (ESI) m / z C 11 H 13 N3NaO3S + [M+Na] + Theoretical value: 290.0570, measured value: 290.0575.

[0054] Example 6

[0055] Under an argon atmosphere, 161.3 mg (1.0 mmol) of oxyalkylisourea (Formula I-2), 189.5 mg (0.5 mmol) of bezafibrate (Formula II-6), and 0.5 mL of 1,4-dioxane were sequentially added to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction tube was sealed, and the mixture was stirred at 70 °C for 12 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using petroleum ether and ethyl acetate in a 1:1 volume ratio to obtain the yellow solid product of Formula III-6 in 95% (99% D) yield.

[0056]

[0057] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ = 7.60 (d, J = 8.5Hz, 2H), 7.28 (d, J = 8.5 Hz, 2H), 7.01 (d, J = 8.6 Hz, 2H), 6.77-6.68 (m,3H), 3.55 (q, J = 6.7 Hz, 2H), 2.78 (t, J= 7.1 Hz, 2H), 1.54 (s, 6H); 13 C NMR (100 MHz, CDCl3) δ = 174.8, 166.5, 153.9, 137.5, 133.0, 132.6, 129.5, 128.6,128.4, 119.5, 79.1, 77.4, 52.5-50.3 (m), 41.3, 34.7, 25.3; HRMS (ESI) m / zC 20 H 20 D3ClNO4 + [M+Na] + Theoretical value: 379.1498, measured value: 379.1494.

[0058] Example 7

[0059] Under an argon atmosphere, 161.3 mg (1.0 mmol) of oxyalkylisourea (Formula I-2), 77.1 mg (0.5 mmol) of 4-aminobenzoic acid (Formula II-7), and 0.5 mL of 1,4-dioxane were sequentially added to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction tube was sealed, and the mixture was stirred at 70 °C for 12 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using a dichloromethane and methanol eluent in a volume ratio of 10:1 to obtain the yellow solid product (Formula III-7) in 72% (99% D).

[0060]

[0061] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ = 7.84 (d, J = 8.6Hz, 2H), 6.62 (d, J = 8.7 Hz, 2H), 4.02 (brs, 2H); 13 C NMR (100 MHz, CDCl3) δ= 167.3, 151.0, 131.7, 119.7, 113.9, 51.4-50.5 (m); HRMS (ESI) m / z C8H6D3NNaO2 + [M+Na] + Theoretical value: 177.0714, measured value: 177.0716.

[0062] Example 8

[0063] Under an argon atmosphere, 161.3 mg (1.0 mmol) of oxyalkylisourea (Formula I-2), 134.2 mg (0.5 mmol) of 5-dimethylamino-1-naphthalenesulfonic acid (Formula II-8), and 3.0 mL of 1,4-dioxane were sequentially added to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction tube was sealed, and the mixture was stirred at 80 °C for 12 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using petroleum ether and ethyl acetate in a volume ratio of 2:1 to obtain the yellow solid product (Formula III-8) in 92% (99% D) yield.

[0064]

[0065] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ = 8.61 (d, J = 8.5Hz, 1H), 8.31-8.23 (m, 2H), 7.57 (m, 2H), 7.21 (dd, J = 7.5, 1.0 Hz, 1H),2.89 (s, 6H); 13 C NMR (100 MHz, CDCl3) δ = 151.9, 131.7, 130.9, 130.6, 130.1,130.0, 128.9, 123.1, 119.5, 115.7, 56.1-53.9 (m), 45.5; HRMS (APCI) m / zC 17 H 19 N2O3S + [M+H] + Theoretical value: 331.1111, measured value: 331.1115.

[0066] Example 9

[0067] Under an argon atmosphere, 161.3 mg (1.0 mmol) of alkylisourea (Formula I-2), 133.6 mg (0.5 mmol) of diphenyl phosphate (Formula II-4), and 0.5 mL of 1,4-dioxane were sequentially added to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction tube was sealed, and the mixture was stirred at 70 °C for 12 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using petroleum ether and ethyl acetate in a 1:1 volume ratio to obtain a white solid product (Formula III-9) in 99% (99% D) yield.

[0068]

[0069] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ = 7.31 (t, J = 7.8Hz, 4H), 7.22-7.12 (m, 6H); 13 C NMR (100 MHz, CDCl3) δ = 150.7, 150.6, 129.9,125.5, 125.5, 120.1, 120.1, 54.8; 31 p NMR (162 MHz, CDCl3) δ = -10.79; HRMS(ESI) m / z C 13 H 11 D3O4P + [M+H] + Theoretical value: 268.0813, measured value: 268.0806.

[0070] Example 10

[0071] Under an argon atmosphere, 161.3 mg (1.0 mmol) of alkylisourea (Formula I-2), 220.6 mg (0.5 mmol) of benzbromarone (Formula II-2), and 0.5 mL of 1,4-dioxane were sequentially added to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction tube was sealed, and the reaction was stirred at 110 °C for 12 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using petroleum ether and ethyl acetate in a volume ratio of 20:1 to obtain a white solid product of Formula III-10 in 99% (99% D) yield.

[0072]

[0073] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ = 7.97 (s, 2H),7.47 (d, J = 8.2 Hz, 1H), 7.41 (d, J = 7.1 Hz, 1H), 7.31-7.18 (m, 2H), 2.89(q, J = 7.5 Hz, 2H), 1.35 (t, J = 7.5 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ =188.0, 166.9, 157.7, 153.7, 137.2, 133.7, 126.4, 124.8, 123.9, 121.1, 118.5,115.4, 111.2, 60.6-59.7 (m), 22.1, 12.3; HRMS (APCI) m / z C 18 H 12 D3Br2O3 + [M+H] + Theoretical value: 439.9571, measured value: 439.9568.

[0074] Example 11

[0075] Under an argon atmosphere, 161.3 mg (1.0 mmol) of oxyalkylisourea (Formula I-2), 71.1 mg (0.5 mmol) of 4-aminobenzylthiophenol (Formula II-9), and 0.5 mL of 1,4-dioxane were sequentially added to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction tube was then sealed and incubated at 50 °C. o The reaction mixture was stirred at C for 12 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate and water, dried over anhydrous sodium sulfate and concentrated. The solution was then purified by column chromatography using petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain the yellow liquid product shown in Formula III-11, with a yield of 93% (99% D).

[0076]

[0077] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ = 7.18 (d, J = 8.4Hz, 2H), 6.62 (d, J = 8.5 Hz, 2H), 3.57 (brs, 2H);13 C NMR (100 MHz, CDCl3) δ= 145.2, 131.1, 125.8, 115.8, 19.4-16.6 (m); HRMS (ESI) m / z C7H6D3NNaS + [M+Na] + Theoretical value: 165.0536, measured value: 165.0535.

[0078] Example 12

[0079] Under an argon atmosphere, 161.3 mg (1.0 mmol) of oxyalkylisourea (Formula I-2), 75.7 mg (0.5 mmol) of 3-mercapto-1-hexanol (Formula II-10), and 0.5 mL of 1,4-dioxane were sequentially added to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction tube was sealed, and the mixture was stirred at 50 °C for 12 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using petroleum ether and ethyl acetate in a volume ratio of 2:1 to obtain the yellow liquid product (Formula III-12) in 72% (99% D).

[0080]

[0081] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ = 3.86-3.69 (m,2H), 2.69-2.59 (m, 1H), 2.44 (brs, 1H), 1.90-1.77 (m, 1H), 1.77-1.63 (m, 1H),1.62-1.35 (m, 4H), 0.89 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ =61.2, 43.6, 36.9, 36.3, 20.1, 14.0, 12.1-11.1 (m); HRMS (APCI) m / z C7H 14 D3OS + [M+H] + Theoretical value: 152.1183, measured value: 152.1188.

[0082] Example 13

[0083] Under an argon atmosphere, 161.3 mg (1.0 mmol) of oxyalkylisourea (Formula I-2), 199.2 mg (0.5 mmol) of celecoxib (Formula II-11), and 0.5 mL of 1,4-dioxane were sequentially added to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction tube was sealed, and the mixture was stirred at 70 °C for 12 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using petroleum ether and ethyl acetate in a 1:1 volume ratio to obtain the yellow solid product (Formula III-13) in 71% (99% D).

[0084]

[0085] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ = 7.84 (d, J = 8.7Hz, 2H), 7.47 (d, J = 8.7 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 8.2Hz, 2H), 6.74 (s, 1H), 4.82 (brs, 1H), 2.37 (s, 3H); 13 C NMR (100 MHz, CDCl3)δ = 145.4, 144.2, 142.7, 139.9, 138.5, 129.9, 128.8, 128.3, 125.8, 125.7,121.2, 106.8-105.9 (m), 29.3-27.5 (m), 21.4; 19 F NMR (376 MHz, CDCl3) δ = -62.14; HRMS (ESI) m / z C 18 H 13 D3F3N3NaO2S + [M+Na] + Theoretical value: 421.0996, measured value: 421.0999.

[0086] Example 14

[0087] Under an argon atmosphere, 161.3 mg (1.0 mmol) of oxyalkylisourea (Formula I-2), 100.1 mg (0.5 mmol) of saccharin (Formula II-12), and 0.5 mL of 1,4-dioxane were sequentially added to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction tube was sealed, and the mixture was stirred at 70 °C for 12 hours. After the reaction was complete, the reaction solution was extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using petroleum ether and ethyl acetate in a volume ratio of 4:1 to obtain a yellow solid product (Formula III-14) in 75% (99% D).

[0088]

[0089] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ = 8.03 (dd, J =7.1, 1.5 Hz, 1H), 7.94-7.89 (m, 1H), 7.83 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ= 158.8, 137.7, 134.8, 134.4, 127.6, 125.2, 121.1, 22.8-22.5 (m); HRMS (ESI)m / z C8H4D3NNaO3S + [M+Na] + Theoretical value: 223.0227; Measured value: 223.0229.

[0090] Example 15

[0091] Under an argon atmosphere, 161.3 mg (1.0 mmol) of oxyalkylisourea (Formula I-2), 82.1 mg (0.5 mmol) of phthalimide (Formula II-13), and 0.5 mL of 1,4-dioxane were sequentially added to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction tube was sealed, and the reaction was stirred at 70 °C for 12 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using petroleum ether and ethyl acetate in a volume ratio of 8:1 to obtain the yellow solid product (Formula III-15) in 90% (99% D) yield.

[0092]

[0093] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1H NMR (400 MHz, CDCl3) δ = 7.85-7.79 (m, 2H), 7.71-7.66 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ = 168.6, 134.0, 132.4,123.3, 23.8-22.9 (m); HRMS (ESI) m / z C9H4D3NNaO2 + [M+Na] + Theoretical value: 187.0557; Measured value: 187.0551.

[0094] Example 16

[0095] Under an argon atmosphere, 159.2 mg (1.0 mmol) of oxyalkylisourea (Formula I-3), 186.4 mg (0.5 mmol) of indomethacin (Formula II-14), and 0.5 mL of 1,4-dioxane were sequentially added to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction tube was sealed and stirred at 70 °C for 12 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using petroleum ether and ethyl acetate in a volume ratio of 4:1 to obtain the yellow solid product (Formula III-16) in 99% yield.

[0096]

[0097] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ = 7.64 (d, J = 8.5Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 2.6 Hz, 1H), 6.85 (s, 1H), 6.65 (dd, J = 9.0, 2.5 Hz, 1H), 3.87 (s, 1H), 3.81 (s, 3H), 3.66 (s, 2H), 3.51 (s, 2H), 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3) δ = 171.3, 168.2, 156.1,139.2, 135.9, 133.9, 131.2, 130.8, 130.6, 129.1, 114.9, 112.5, 111.6, 101.3,55.7, 52.1, 13.3; HRMS (ESI) m / z C 19 13 CH 19 ClNO4 + [M+H] + Theoretical value: 373.1031, measured value: 373.1025.

[0098] Example 17

[0099] Under an argon atmosphere, 159.2 mg (1.0 mmol) of oxyalkylisourea (Formula I-3), 165.7 mg (0.5 mmol) of febuxostat (Formula II-1), and 0.5 mL of 1,4-dioxane were sequentially added to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction tube was sealed, and the mixture was stirred at 70 °C for 12 hours. After the reaction was complete, the reaction solution was extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using petroleum ether and ethyl acetate in a volume ratio of 4:1 to obtain a white solid product (Formula III-17) in 99% yield.

[0100]

[0101] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, DMSO) δ = 8.22 (d, J = 2.3Hz, 1H), 8.16 (dd, J = 8.9, 2.4 Hz, 1H), 7.33 (d, J = 9.0 Hz, 1H), 4.00 (s,1.5H), 3.98 (d, J = 6.5 Hz, 2H), 3.63 (s, 1.5H), 2.64 (s, 3H), 2.15-2.02 (m,1H), 1.01 (d, J = 6.7 Hz, 6H); 13C NMR (100 MHz, DMSO) δ = 166.7, 162.1,161.8, 160.3, 133.0, 131.5, 125.0, 120.9, 115.3, 113.8, 101.5, 75.1, 52.3,27.6, 18.8, 17.1; HRMS (ESI) m / z C 16 13 CH 19 N2O3S + [M+H] + Theoretical value: 332.1144, measured value: 332.1137.

[0102] Example 18

[0103] Under an argon atmosphere, 159.2 mg (1.0 mmol) of oxyalkylisourea (Formula I-3), 110.7 mg (0.5 mmol) of 4-tert-butyl-2,6-formylphenol (Formula II-15), and 0.5 mL of 1,4-dioxane were sequentially added to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction tube was sealed, and the mixture was stirred at 110 °C for 12 hours. After the reaction was complete, the reaction solution was extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using petroleum ether and ethyl acetate in a volume ratio of 20:1 to obtain the yellow solid product (Formula III-18) in 99% yield.

[0104]

[0105] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ = 10.36 (s, 2H), 8.08 (s, 2H), 4.20 (s, 2H), 3.84 (s, 2H), 1.30 (s, 9H); 13 C NMR (100 MHz, CDCl3) δ = 188.7, 163.6, 148.3, 132.0, 129.5, 66.7, 34.8, 31.1; HRMS (ESI) m / z C 12 13 CH 17 O + [M+H] + Theoretical value: 222.1206, measured value: 222.1200.

[0106] Example 19

[0107] Under an argon atmosphere, 159.2 mg (1.0 mmol) of oxyalkylisourea (Formula I-3), 189.7 mg (0.5 mmol) of 1-thio-BD-glucosetetraacetate (Formula II-3), and 0.5 mL of 1,4-dioxane were sequentially added to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction tube was sealed, and the reaction was stirred at 50 °C for 12 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using petroleum ether and ethyl acetate in a volume ratio of 10:1 to obtain the yellow solid product shown in Formula III-19, with a yield of 89%.

[0108]

[0109] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, DMSO- d 6) δ = 5.30 (t, J =9.3 Hz, 1H), 4.91 (dt, J = 12.7, 9.6 Hz, 2H), 4.82 (dd, J = 10.0, 4.2 Hz, 1H), 4.13 (dd, J = 12.5, 5.5 Hz, 1H), 4.08-3.97 (m, 2H), 2.25 (s, 1H), 2.02(d, J = 2.6 Hz, 6H), 1.99 (s, 4H), 1.95 (s, 3H), 1.90 (s, 2H); 13 C NMR (100MHz, DMSO- d 6) δ = 170.5, 170.0, 169.8, 169.6, 81.6, 74.8, 73.4, 69.4, 68.6,62.5, 23.3-20.6 (m), 11.1; HRMS (ESI) m / z C 14 13 CH 23 NaO9S + [M+H] + Theoretical value: 402.0910, measured value: 402.0899.

[0110] Example 20

[0111] Under an argon atmosphere, 159.2 mg (1.0 mmol) of oxyalkylisourea (Formula I-3), 91.1 mg (0.5 mmol) of 4-mercapto-N-methylbenzamide (Formula II-16), and 0.5 mL of 1,4-dioxane were sequentially added to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction tube was then sealed and incubated at 50 °C. o The reaction mixture was stirred at C for 12 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate and water, dried over anhydrous sodium sulfate and concentrated. The solution was then purified by column chromatography using petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain the white solid product shown in Formula III-20, with a yield of 99%.

[0112]

[0113] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, DMSO- d 6) δ = 9.93 (s, 1H), 7.54 (d, J = 8.7 Hz, 2H), 7.21 (d, J = 8.7 Hz, 2H), 2.60 (s, 1H), 2.25 (s, 2H), 2.03 (s, 3H); 13 C NMR (100 MHz, DMSO- d 6) δ = 168.3, 137.0, 131.5, 127.3,119.8, 24.1, 15.7; HRMS (ESI) m / z C8 13 CH 12 NOS + [M+H] + Theoretical value: 183.0668, measured value: 183.0672.

[0114] Example 21

[0115] Under an argon atmosphere, 159.2 mg (1.0 mmol) of oxyalkylisourea (Formula I-3), 106.3 mg (0.5 mmol) of 2-chlorothiophene-5-sulfonamide (Formula II-17), and 0.5 mL of 1,4-dioxane were sequentially added to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction tube was sealed, and the reaction was stirred at 70 °C for 12 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using petroleum ether and ethyl acetate in a volume ratio of 4:1 to obtain the yellow liquid product (Formula III-21) in 99% yield.

[0116]

[0117] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ = 7.39 (d, J = 4.0Hz, 1H), 6.93 (d, J = 4.0 Hz, 1H), 5.03-4.93 (m, 1H), 2.89 (d, J = 5.3 Hz, 2H), 2.54 (d, J = 5.3 Hz, 2H); 13 C NMR (100 MHz, CDCl3) δ = 137.7, 137.4,131.9, 127.0, 29.5; HRMS (ESI) m / z C4 13 CH7ClNNaO2S2 + [M+Na] + Theoretical value: 234.9454, measured value: 234.9470.

[0118] Example 22

[0119] Under an argon atmosphere, 162.3 mg (1.0 mmol) of oxyalkylisourea (Formula I-4), 161.2 mg (0.5 mmol) of N-tert-butyloxycarbonyl-L-tryptophan (Formula II-18), and 0.5 mL of 1,4-dioxane were sequentially added to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction tube was sealed, and the reaction was stirred at 70 °C for 12 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain a white solid product (Formula III-22) in 89% (99% D).

[0120]

[0121] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, DMSO- d 6) δ = 10.85 (brs,1H), 7.48 (d, J = 7.8 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 7.8 Hz, 1H), 7.15 (d,J = 2.3 Hz, 1H), 7.07 (m, 1H), 6.99 (m, 1H), 4.20 (brs, 1H), 3.11 (dd, J = 14.5, 5.3 Hz, 1H), 3.04-2.97 (m, 1H), 1.33 (s, 9H); 13 C NMR (100MHz, DMSO- d 6) δ = 155.8, 136.6, 127.5, 124.2, 121.4, 118.8, 118.4, 111.9,110.2, 78.7, 55.1, 52.1, 51.9, 51.7, 51.4, 51.2, 51.0, 50.8, 28.6, 27.3; HRMS(ESI) m / z C 16 13 CH 19 D3N2NaO4 + [M+Na] + Theoretical value: 345.1694, measured value: 345.1703.

[0122] Example 23

[0123] Under an argon atmosphere, 162.3 mg (1.0 mmol) of oxyalkylisourea (Formula I-4), 77.6 mg (0.5 mmol) of 4-aminobenzoic acid (Formula II-7), and 0.5 mL of 1,4-dioxane were sequentially added to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction tube was sealed, and the mixture was stirred at 70 °C for 12 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using petroleum ether and ethyl acetate in a 1:1 volume ratio to obtain a white solid product (Formula III-23) in 83% (99% D) yield.

[0124]

[0125] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, DMSO- d 6) δ = 7.63 (d, J =8.7 Hz, 2H), 6.55 (d, J = 8.7 Hz, 2H), 5.96 (s, 2H); 13 C NMR (100 MHz, DMSO- d6) δ = 166.8, 153.9, 131.5, 116.2, 113.1, 51.3, 51.1, 51.0, 50.8, 50.7,50.6, 50.4; HRMS (ESI) m / z C7 13 CH7D3NO2 + [M+H] + Theoretical value: 156.0928, measured value: 156.0935.

[0126] Example 24

[0127] Under an argon atmosphere, 162.3 mg (1.0 mmol) of oxyalkylisourea (Formula I-4), 134.1 mg (0.5 mmol) of diphenyl phosphate (Formula II-4), and 0.5 mL of 1,4-dioxane were sequentially added to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction tube was sealed, and the reaction was stirred at 70 °C for 12 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using petroleum ether and ethyl acetate in a 1:1 volume ratio to obtain a white solid product of Formula III-24 in 77% (99% D) yield.

[0128]

[0129] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, DMSO- d 6) δ = 7.44 (t, J =7.9 Hz, 4H), 7.30-7.22 (m, 6H); 13 C NMR (100 MHz, DMSO- d 6) δ = 150.5, 130.6,126.0, 120.4, 55.8-54.9; 31 P NMR (162 MHz, DMSO- d 6) δ = -10.79; HRMS (ESI) m / z C 12 13 CH 10 D3O4P + [M+H] + Theoretical value: 269.0846, measured value: 269.0838.

[0130] Example 25

[0131] Under an argon atmosphere, 162.3 mg (1.0 mmol) of alkylisourea (Formula I-4), 221.1 mg (0.5 mmol) of benzbromarone (Formula II-2), and 0.5 mL of 1,4-dioxane were sequentially added to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction tube was sealed, and the reaction was stirred at 110 °C for 12 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using petroleum ether and ethyl acetate in a volume ratio of 20:1 to obtain the yellow solid product of Formula III-25 in 98% (99% D) yield.

[0132]

[0133] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, DMSO- d 6) δ = 7.17 (s, 2H), 6.82 (d, J = 8.1 Hz, 1H), 6.65-6.58 (m, 1H), 6.52 (m, 1H), 6.48-6.42 (m, 1H), 1.96 (q, J = 7.5 Hz, 2H), 0.43 (t, J = 7.5 Hz, 3H); 13 C NMR (100 MHz, DMSO- d 6)δ = 187.9, 167.0, 157.3, 153.5, 137.7, 133.6, 126.6, 125.3, 124.4, 121.2,118.4, 115.4, 111.7, 60.8, 60.7, 60.5, 60.4, 60.2, 60.1, 59.9, 22.0, 12.3;HRMS (ESI) m / z C 17 13 CH 12 D3Br2O3 + [M+H] + Theoretical value: 440.9604, measured value: 440.9609.

[0134] Example 26

[0135] Under an argon atmosphere, 162.3 mg (1.0 mmol) of oxyalkylisourea (Formula I-4), 76.1 mg (0.5 mmol) of 6-mercaptohexane-1-ol (Formula II-19), and 0.5 mL of 1,4-dioxane were sequentially added to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction tube was sealed, and the mixture was stirred at 70 °C for 12 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using petroleum ether and ethyl acetate in a volume ratio of 2:1 to obtain the yellow solid product (Formula III-26) in 82% (99% D).

[0136]

[0137] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, DMSO- d 6) δ = 4.37 (t, J =5.2 Hz, 1H), 3.45-3.39 (m, 2H), 2.48 (m, J = 7.3, 4.3 Hz, 2H), 1.55 (p, J =7.4, 6.9 Hz, 2H), 1.50-1.28 (m, 6H); 13 C NMR (100 MHz, DMSO- d 6) δ = 61.2,33.6, 33.0, 29.2, 29.2, 28.6, 25.6, 15.1, 14.9, 14.7, 14.5, 14.3, 14.0, 13.8;HRMS (ESI) m / z C6 13 CH 14 D3OS + [M+H] + Theoretical value: 153.1216, measured value: 153.1219.

[0138] Example 27

[0139] Under an argon atmosphere, 142.4 mg (0.9 mmol) of oxyalkylisourea (Formula I-1), 45.6 mg (0.3 mmol) of 4-methoxyphenylboronic acid (Formula IV-1), 22.7 mg (0.03 mmol) of 1,1'-bis(di-cyclohexylphosphino)ferrocene palladium dichloride (Formula Pd-1), 146.5 mg (0.75 mmol) of N-methyldicyclohexylamine (Cy2NMe), and 1.5 mL of 1,3-dimethyl-2-imidazoline were sequentially added to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction tube was then sealed and incubated at 80 °C. o The reaction was stirred at C for 16 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate and water, dried with anhydrous sodium sulfate and concentrated. The solution was then purified by column chromatography using petroleum ether and ethyl acetate in a volume ratio of 100:1 to obtain the white liquid product shown in Formula V-1, with a yield of 56%.

[0140]

[0141] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ = 7.09 (d, J = 8.2Hz, 2H), 6.81 (d, J = 8.4 Hz, 2H), 3.79 (s, 3H), 2.29 (s, 3H); 13 C NMR (100MHz, CDCl3) δ = 157.6, 130.0, 127.9, 113.8, 55.4, 20.6.

[0142] Example 28

[0143] Under an argon atmosphere, 142.4 mg (0.9 mmol) of oxoalkylisourea (Formula I-1), 73.8 mg (0.3 mmol) of 1-pyreneboronic acid (Formula IV-2), 22.7 mg (0.03 mmol) of 1,1'-bis(di-cyclohexylphosphino)ferrocene palladium dichloride (Formula Pd-1), 146.5 mg (0.75 mmol) of N-methyldicyclohexylamine, and 1.5 mL of 1,3-dimethyl-2-imidazoline were sequentially added to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction tube was then sealed and incubated at 80 °C. o The reaction mixture was stirred at C for 16 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate and water, dried over anhydrous sodium sulfate and concentrated. The solution was then purified by column chromatography using petroleum ether as the eluent to obtain the white solid product shown in Formula V-1, with a yield of 74%.

[0144]

[0145] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ = 8.27-8.22 (m,1H), 8.22-8.17 (m, 2H), 8.15-8.08 (m, 2H), 8.09-8.00 (m, 3H), 7.88 (d, J =7.7 Hz, 1H), 3.00 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ = 132.3, 131.5, 131.1,129.8, 129.3, 127.9, 127.6, 127.5, 127.2, 126.5, 125.8, 125.0, 124.9, 124.9,124.9, 124.8, 124.7, 123.8, 19.9.

[0146] Example 29

[0147] Under an argon atmosphere, 142.4 mg (0.9 mmol) of oxyalkylisourea (Formula I-1), 59.4 mg (0.3 mmol) of 2-biphenylboronic acid (Formula IV-3), 22.7 mg (0.03 mmol) of 1,1'-bis(di-cyclohexylphosphino)ferrocene palladium dichloride (Formula Pd-1), 146.5 mg (0.75 mmol) Cy2NMe, and 1.5 mL of 1,3-dimethyl-2-imidazoline were sequentially added to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction tube was then sealed and incubated at 80 °C. o The reaction was carried out at C for 16 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate and water, dried over anhydrous sodium sulfate and concentrated. Petroleum ether was used as the eluent and the product was purified by column chromatography to obtain the white solid product shown in formula V-3, with a yield of 52%.

[0148]

[0149] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ = 7.51-7.43 (m,2H), 7.43-7.37 (m, 3H), 7.35-7.31 (m, 2H), 7.30 (dd, J = 3.0, 1.4 Hz, 2H),2.34 (s, 3H); 13C NMR (100 MHz, CDCl3) δ = 142.1, 142.1, 135.5, 130.4, 129.9, 129.3, 128.2, 127.4, 126.9, 125.9, 20.6.

[0150] Example 30

[0151] Under an argon atmosphere, 142.4 mg (0.9 mmol) of oxyalkylisourea (Formula I-1), 72.9 mg (0.3 mmol) of pinacol 5-indoleboronic acid (Formula IV-4), 22.7 mg (0.03 mmol) of 1,1'-bis(di-cyclohexylphosphino)ferrocene palladium dichloride (Formula Pd-1), 106.8 mg (0.75 mmol) of magnesium acetate, and 1.5 mL of 1,3-dimethyl-2-imidazoline were sequentially added to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction tube was then sealed and incubated at 80 °C. o The reaction was carried out at C for 16 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate and water, dried with anhydrous sodium sulfate and concentrated. The solution was then purified by column chromatography using petroleum ether and ethyl acetate in a volume ratio of 10:1 to obtain the white solid product shown in Formula V-4, with a yield of 80%.

[0152]

[0153] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ = 10.76 (brs, 1H),8.19 (d, J = 1.9 Hz, 1H), 7.76 (dd, J = 2.0, 0.9 Hz, 1H), 7.34 (d, J = 3.5Hz, 1H), 6.43 (d, J = 3.4 Hz, 1H), 2.45 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ =147.5, 143.6, 129.1, 125.4, 124.9, 120.4, 100.2, 18.7.

[0154] Example 31

[0155] Under an argon atmosphere, 142.4 mg (0.9 mmol) of oxoalkylisourea (Formula I-1), 73.8 mg (0.3 mmol) of benzo[C][1,2,5]diazol-5-boronic acid pinacol ester (Formula IV-5), 22.7 mg (0.03 mmol) of 1,1'-bis(di-cyclohexylphosphino)ferrocene palladium dichloride (Formula Pd-1), 106.8 mg (0.75 mmol) magnesium acetate, and 1.5 mL of 1,3-dimethyl-2-imidazoline were sequentially added to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction tube was then sealed and incubated at 80 °C. o The reaction was carried out at C for 16 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate and water, dried with anhydrous sodium sulfate and concentrated. The solution was then purified by column chromatography using petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain the white solid product shown in Formula V-5, with a yield of 50%.

[0156]

[0157] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ = 7.71 (dd, J =9.2, 1.0 Hz, 1H), 7.52 (d, J = 1.3 Hz, 1H), 7.24 (d, J = 1.4 Hz (1H), 2.45 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ = 149.6, 148.4, 142.1, 135.1, 115.9, 113.5, 22.5.

[0158] Example 32

[0159] Under an argon atmosphere, 145.2 mg (0.9 mmol) of oxoalkylisourea (Formula I-2), 116.8 mg (0.3 mmol) of 6-(4-Boc-piperazin-1-yl)pyridine-3-boronic acid (Formula IV-6), 22.7 mg (0.03 mmol) of 1,1'-bis(di-cyclohexylphosphino)ferrocene palladium dichloride (Formula Pd-1), 106.8 mg (0.75 mmol) magnesium acetate, and 1.5 mL of 1,3-dimethyl-2-imidazoline were sequentially added to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction tube was then sealed and incubated at 80 °C. oThe reaction was carried out at C for 16 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate and water, dried with anhydrous sodium sulfate and concentrated. The solution was then purified by column chromatography using petroleum ether and ethyl acetate in a volume ratio of 1:1 to obtain a white solid product as shown in Formula V-6, with a yield of 46% (99% D).

[0160]

[0161] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ = 7.98 (s, 1H),7.33-7.16 (m, 1H), 6.56 (s, 1H), 3.50 (dd, J = 6.5, 3.9 Hz, 4H), 3.41 (dd, J = 7.1, 3.5 Hz, 4H), 1.44 (d, J = 1.5 Hz, 9H); 13 C NMR (100 MHz, CDCl3) δ =157.9, 154.8, 147.7, 138.5, 122.6, 107.2, 79.8, 45.7, 28.5, 17.3-16.3.

[0162] Example 33

[0163] Under an argon atmosphere, 145.2 mg (0.9 mmol) of alkylisourea (Formula I-2), 76.5 mg (0.3 mmol) of pinacol 6-quinoline borate (Formula IV-7), 22.7 mg (0.03 mmol) of 1,1'-bis(di-cyclohexylphosphino)ferrocene palladium dichloride (Formula Pd-1), 106.8 mg (0.75 mmol) of magnesium acetate, and 1.5 mL of 1,3-dimethyl-2-imidazoline were sequentially added to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction tube was then sealed and incubated at 80 °C. o The reaction was carried out at C for 16 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate and water, dried with anhydrous sodium sulfate and concentrated. The solution was then purified by column chromatography using petroleum ether and ethyl acetate in a volume ratio of 3:1 to obtain a white solid product as shown in Formula V-7, with a yield of 83% (99% D).

[0164]

[0165] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ = 8.85 (dd,J =4.2, 1.7 Hz, 1H), 8.11-8.03 (m, 1H), 8.00 (d, J = 8.5 Hz, 1H), 7.63-7.48 (m,2H), 7.35 (dd, J = 8.3, 4.2 Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ = 149.7, 147.1, 136.4, 135.5, 131.9, 129.2, 128.5, 126.7, 121.2, 21.9-21.6.

[0166] Example 34

[0167] Under an argon atmosphere, 145.2 mg (0.9 mmol) of oxyalkylisourea (Formula I-2), 76.8 mg (0.3 mmol) of pinacol quinoxaline-6-borate (Formula IV-8), 22.7 mg (0.03 mmol) of 1,1'-bis(di-cyclohexylphosphino)ferrocene palladium dichloride (Formula Pd-1), 106.8 mg (0.75 mmol) of magnesium acetate, and 1.5 mL of 1,3-dimethyl-2-imidazoline were sequentially added to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction tube was then sealed at 80°C. o The reaction was carried out at C for 16 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate and water, dried with anhydrous sodium sulfate and concentrated. The solution was then purified by column chromatography using petroleum ether and ethyl acetate in a volume ratio of 2:1 to obtain a white solid product as shown in Formula V-8, with a yield of 53% (99% D).

[0168]

[0169] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ = 8.81-8.71 (m,2H), 7.97 (d, J = 8.6 Hz, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.58 (dd, J = 8.6, 1.9 Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ = 145.0, 144.2, 143.2, 141.6, 140.6,132.5, 129.1, 128.4, 21.3-20.9 (m).

[0170] Example 35

[0171] Under an argon atmosphere, 143.3 mg (0.9 mmol) of oxyalkylisourea (Formula I-3), 110.2 mg (0.3 mmol) of pinacol arylboronic acid (Formula IV-9), 22.7 mg (0.03 mmol) of 1,1'-bis(di-cyclohexylphosphino)ferrocene palladium dichloride (Formula Pd-1), 106.8 mg (0.75 mmol) of magnesium acetate, and 1.5 mL of 1,3-dimethyl-2-imidazoline were sequentially added to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction tube was then sealed at 80°C. o The reaction was carried out at C for 16 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate and water, dried with anhydrous sodium sulfate and concentrated. The solution was then purified by column chromatography using petroleum ether and ethyl acetate in a volume ratio of 2:1 to obtain a white solid product as shown in Formula V-9, with a yield of 60%.

[0172]

[0173] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ = 7.67 (d, J = 8.3Hz, 2H), 7.31-7.23 (m, 2H), 3.08-2.99 (m, 4H), 2.56 (s, 1H), 2.24 (s, 2H), 1.61-1.46 (m, 4H), 0.85 (t, J = 7.4 Hz, 7H). 13 C NMR (100 MHz, CDCl3) δ =143.0, 137.3, 129.6, 127.2, 50.1, 22.1, 21.6, 11.3; HRMS (APCI) m / zC 12 13 CH 22 NO2S + [M+H] + Theoretical value: 257.1399, measured value: 257.1408.

[0174] Example 36

[0175] Under an argon atmosphere, 143.3 mg (0.9 mmol) of oxyalkylisourea (Formula I-3), 135.7 mg (0.3 mmol) of pinacol arylboronic acid (Formula IV-10), 22.7 mg (0.03 mmol) of 1,1'-bis(di-cyclohexylphosphino)ferrocene palladium dichloride (Formula Pd-1), 106.8 mg (0.75 mmol) of magnesium acetate, and 1.5 mL of 1,3-dimethyl-2-imidazoline were sequentially added to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction tube was then sealed and incubated at 80 °C. o The reaction was carried out at C for 16 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate and water, dried with anhydrous sodium sulfate and concentrated. The solution was then purified by column chromatography using petroleum ether and ethyl acetate in a volume ratio of 10:1 to obtain a white solid product as shown in formula V-10, with a yield of 57%.

[0176]

[0177] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ = 7.76 (d, J = 8.7Hz, 2H), 7.68 (d, J = 8.2 Hz, 2H), 7.28 (dd, J = 5.1, 3.0 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 5.10 (m, J = 6.2 Hz, 1H), 2.59 (s, 1H), 2.28 (s, 1H), 1.67 (s,6H), 1.21 (d, J = 6.3 Hz, 6H); 13 C NMR (100 MHz, CDCl3) δ = 195.4, 173.3,159.4, 142.5, 135.5, 132.0, 130.1, 130.0, 129.0, 128.9, 117.2, 79.4, 69.4,25.4, 21.7; HRMS (APCI) m / z C 20 13 CH 25 O4 + [M+H] + Theoretical value: 342.1781, measured value: 342.1782.

[0178] Example 37

[0179] Under an argon atmosphere, 143.3 mg (0.9 mmol) of oxyalkylisourea (Formula I-3), 100.3 mg (0.3 mmol) of pinacol arylboronic acid (Formula IV-11), 22.7 mg (0.03 mmol) of 1,1'-bis(di-cyclohexylphosphino)ferrocene palladium dichloride (Formula Pd-1), 106.8 mg (0.75 mmol) of magnesium acetate, and 1.5 mL of 1,3-dimethyl-2-imidazoline were sequentially added to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction tube was then sealed and incubated at 80 °C. o The reaction was carried out at C for 16 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate and water, dried with anhydrous sodium sulfate and concentrated. The solution was then purified by column chromatography using petroleum ether and ethyl acetate in a volume ratio of 10:1 to obtain a white solid product as shown in formula V-11, with a yield of 49%.

[0180]

[0181] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ = 7.06-7.00 (m,2H), 6.76 (d, J = 8.5 Hz, 2H), 4.24 (q, J = 7.1 Hz, 2H), 2.43 (s, 2H), 2.11(s, 2H), 1.57 (s, 6H), 1.26 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ =174.5, 153.2, 129.7 (m), 119.5 (m), 79.2, 61.4, 52.5, 25.4, 20.7, 14.2; HRMS(APCI) m / z C 12 13 CH 19 O3 + [M+H] + Theoretical value: 224.1362, measured value: 224.1366.

[0182] Example 38

[0183] Under an argon atmosphere, 146.1 mg (0.9 mmol) of oxyalkylisourea (Formula I-4), 110.2 mg (0.3 mmol) of pinacol arylboronic acid (Formula IV-9), 22.7 mg (0.03 mmol) of 1,1'-bis(di-cyclohexylphosphino)ferrocene palladium dichloride (Formula Pd-1), 106.8 mg (0.75 mmol) of magnesium acetate, and 1.5 mL of 1,3-dimethyl-2-imidazoline were sequentially added to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction tube was then sealed and incubated at 80 °C. o The reaction was carried out at C for 16 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate and water, dried with anhydrous sodium sulfate and concentrated. The solution was then purified by column chromatography using petroleum ether and ethyl acetate in a volume ratio of 2:1 to obtain a white solid product as shown in formula V-12, with a yield of 58% (99% D).

[0184]

[0185] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ = 7.67 (d, J = 8.3Hz, 2H), 7.29-7.22 (m, 2H), 3.08-2.98 (m, 4H), 1.60-1.46 (m, 4H), 0.85 (t, J = 7.4 Hz, 7H); 13 C NMR (100 MHz, CDCl3) δ = 143.1, 137.3, 129.7, 127.2, 50.1,22.1, 21.1-20.4, 11.3; HRMS (APCI) m / z C 12 13 CH 19 D3NO2S + [M+H] + Theoretical value: 260.1588, measured value: 260.1590.

[0186] Example 39

[0187] Under an argon atmosphere, 146.1 mg (0.9 mmol) of oxyalkylisourea (Formula I-4), 135.7 mg (0.3 mmol) of pinacol arylboronic acid (Formula IV-10), 22.7 mg (0.03 mmol) of 1,1'-bis(di-cyclohexylphosphino)ferrocene palladium dichloride (Formula Pd-1), 106.8 mg (0.75 mmol) of magnesium acetate, and 1.5 mL of 1,3-dimethyl-2-imidazoline were sequentially added to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction tube was then sealed at 80°C. o The reaction was carried out at C for 16 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate and water, dried over anhydrous sodium sulfate and concentrated. The solution was then purified by column chromatography using petroleum ether and ethyl acetate in a volume ratio of 10:1 to obtain a white solid product as shown in Formula V-13, with a yield of 61% (99% D).

[0188]

[0189] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ = 7.74 (d, J = 8.8Hz, 2H), 7.66 (d, J = 8.1 Hz, 2H), 7.29-7.23 (m, 2H), 6.85 (d, J = 8.8 Hz, 2H), 5.08 (p, J = 6.3 Hz, 1H), 1.65 (s, 6H), 1.19 (d, J = 6.3 Hz, 6H); 13 C NMR (100 MHz, CDCl3) δ = 195.4, 173.3, 159.4, 142.7, 135.5, 132.0, 131.1, 130.1,129.0, 117.2, 79.4, 69.4, 25.5, 21.6, 20.8 (m); HRMS (APCI) m / z C 20 13 CH 22 D3O4 + [M+H] + Theoretical value: 345.1969, measured value: 345.1975.

[0190] Example 40

[0191] Under an argon atmosphere, 146.1 mg (0.9 mmol) of oxyalkylisourea (Formula I-4), 100.3 mg (0.3 mmol) of pinacol arylboronic acid (Formula IV-11), 22.7 mg (0.03 mmol) of 1,1'-bis(di-cyclohexylphosphino)ferrocene palladium dichloride (Formula Pd-1), 106.8 mg (0.75 mmol) of magnesium acetate, and 1.5 mL of 1,3-dimethyl-2-imidazoline were sequentially added to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction tube was sealed and incubated at 80 °C. o The reaction was carried out at C for 16 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate and water, dried with anhydrous sodium sulfate and concentrated. The solution was then purified by column chromatography using petroleum ether and ethyl acetate in a volume ratio of 10:1 to obtain a white solid product as shown in Formula V-14, with a yield of 58% (99% D).

[0192]

[0193] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ = 7.07-7.00 (m,2H), 6.78-6.73 (m, 2H), 4.24 (q, J = 7.1 Hz, 2H), 1.57 (s, 6H), 1.26 (t, J =7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ = 174.5, 153.2, 129.7, 119.5, 79.2,61.4, 25.4, 20.4, 20.2-19.3, 14.2; HRMS (APCI) m / z C 12 13 CH 16 D3O3 + [M+H] + Theoretical value: 227.1551, measured value: 227.1556.

Claims

1. The application of oxyalkylisoureas in nucleophilic substitution reactions to introduce methyl groups or isotopically labeled methyl groups, characterized in that: The structure of the oxyalkylisourea is shown in Formula I: Among them, R 1 Represents CH3, CD3, 13 CH3 13 Any one of CD3; R 2 and R 3 Each of these can independently represent any one of the following: ethyl, propyl, n-butyl, n-pentyl, benzyl, isopropyl, cyclohexyl, tert-butyl, p-tolyl, 3-dimethylaminopropyl, 2,6-diisopropylphenyl, and trimethylsilyl. The oxyalkyl isourea of ​​Formula I and the nucleophile of Formula II are added to organic solvent A. Under inert gas protection and without the addition of any exogenous base, the reaction is heated and stirred at 50–130°C. After the reaction is completed, the mixture is separated and purified to obtain the methylated or isotopically labeled methylated product of Formula III. The nucleophile is selected from any one of carboxylic acid compounds, sulfonic acid compounds, phosphoric acid compounds, phenolic compounds, thiols, and amine compounds.

2. The application of the oxoalkylisourea according to claim 1 in introducing a methyl group or isotopically labeled methyl group in a nucleophilic substitution reaction, characterized in that: The amount of the oxyalkyl isourea used is 2.0 to 3.0 times the molar amount of the nucleophile reagent.

3. The application of the oxyalkylisourea according to claim 1 in introducing a methyl group or isotopically labeled methyl group in a nucleophilic substitution reaction, characterized in that: The carboxylic acid compound is selected from any one of L-methionine, L-cysteine, L-aspartic acid, L-tryptophan, N-tert-butoxycarbonyl-L-tryptophan, L-phenylalanine, D-homophenylalanine, L-glutamine, (1S)-(-)-camphoric acid, ursolic acid, lithocholic acid, naproxen, indomethacin, isocolic acid, clofibrate, bezafibrate, and febuxostat; or the carboxylic acid compound is selected from the structure R. 4 Compounds with -COOH, where R 4 It is phenyl, or R 4 It is a phenyl group that is substituted with one or more of the following: C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, halogen, cyano, nitro, and amino. The structural formula of the sulfonic acid compound is R. 5 -SO3H, where R 5 Selected from any one of phenyl, C1-C6 alkyl-substituted phenyl, naphthyl, C1-C6 alkyl-substituted naphthyl, and 5-dimethylamino-1-naphthyl; The structural formula of the phosphate compound is (R 6 O)2-P(O)-OH, where R 6 Selected from phenyl and C1-C4 alkyl-substituted phenyl groups; The phenolic compound is selected from any one of estrone, coumarin, maltol, vanillin, benzo[a]chromone, benzbromarone, and phenolphthalein; or the phenolic compound is selected from the compound with the structural formula R. 7 Compounds with -OH groups, where R 7 It is phenyl, or R 7 It is a phenyl group that has been substituted with one or more of the following: C1-C6 alkyl, C1-C6 alkoxy, amino, cyano, halogen, aldehyde, and benzoyl. The thiol compound is selected from any one of 1-thio-BD-glucosetetraacetate, methimazole, penicillamine, and captopril; or the thiol compound is selected from the compound with the structural formula R. 8 -SH compounds, where R 8 C3-C8 substituted with alkyl, phenyl, or hydroxyl groups 10 Any one of the alkyl groups, or R 8 It is a phenyl group that is substituted with any one or more of the following: C1 to C6 alkyl, amino, acetamino, hydroxyl, halogen, cyano, and nitro groups; The amine compound is selected from any one of sulfamethoxazole, celecoxib, sulfadiazine, dimethylpyrimidine, phthalimide, saccharin, glibenclamide, and pioglitazone; or the amine compound is selected from the compound with the structural formula […]. The compound in which R 10 It is any one of phenyl, thiophene, or halothiophene, or R 10 It is a phenyl group that is substituted with any one or more of the following: C1-C6 alkyl, C1-C6 alkoxy, amino, acetamino, hydroxyl, halogen, cyano, and nitro.

4. The application of the oxoalkylisourea according to claim 1 in introducing a methyl group or isotopically labeled methyl group in a nucleophilic substitution reaction, characterized in that: The organic solvent A is selected from any one of N,N-dimethylacetamide, N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylpropenylurea, tetrahydrofuran, 1,4-dioxane, 1,3-dioxolane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, acetonitrile, toluene, methyl tert-butyl ether, cyclopentyl methyl ether, dichloromethane, dichloroethane, diethyl ether, ethyl acetate, and dimethyl sulfoxide.

5. The application of oxyalkylisoureas in the Suzuki-Miyaura coupling reaction to introduce methyl groups or isotopically labeled methyl groups, characterized in that: The structure of the oxyalkylisourea is shown in Formula I: Among them, R 1 Represents CH3, CD3, 13 CH3 or 13 Any one of CD3; R 2 and R 3 Each of these can independently represent any one of ethyl, propyl, n-butyl, n-pentyl, benzyl, isopropyl, cyclohexyl, tert-butyl, p-tolyl, 3-dimethylaminopropyl, 2,6-diisopropylphenyl, or trimethylsilyl. The oxyalkylisourea shown in Formula I, along with an arylboride, a palladium catalyst, and a base, is added to organic solvent B and reacted under inert gas protection at 60–130°C with stirring. After the reaction is complete, the mixture is separated and purified to obtain methylated or isotopically labeled methylated products. The arylborides are selected from any one of arylboronic acid, arylboronic acid pinacol ester, arylboronic acid neopentyl glycol ester, and aryltrifluoroborate potassium.

6. The application of the oxyalkylisourea according to claim 5 in introducing methyl groups or isotopically labeled methyl groups in the Suzuki-Miyaura coupling reaction, characterized in that: The aryl borate in the aryl group is selected from phenyl, substituted phenyl, naphthyl, substituted naphthyl, anthracene, substituted anthracene, pyrene, substituted pyrene, biphenyl, substituted biphenyl, carbazolyl, substituted carbazolyl, indolyl, substituted indolyl, quinolinyl, substituted quinolinyl, quinoxalinyl, substituted quinoxalinyl, benzoxadiazolyl, substituted benzoxadiazolyl, pyridinyl, substituted pyridinyl; the substitution refers to being replaced by one or more groups selected from C1-C4 alkyl, C1-C4 alkoxy, hydroxymethyl, halogen, cyano, nitro, amino, acetamino, acetoxy, benzoyl, methanesulfonamide, halogenated phenyl. The arylboride is substituted by any one of the substituents in the form of 6-(4-BOC-1-piperazino)pyridine-3-boronic acid pinacol ester, N,N-dipropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl)benzenesulfonamide, isopropyl 2-methyl-2-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl)benzoyl)phenoxy)propionate or ethyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron-2-yl)phenoxy)propionate.

7. The application of the oxyalkylisourea according to claim 5 in introducing methyl groups or isotopically labeled methyl groups in the Suzuki-Miyaura coupling reaction, characterized in that: The palladium catalyst is selected from palladium chloride, palladium bromide, palladium iodide, palladium acetate, dichloro[2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]palladium(II), 1,1'-bis(diphenylphosphino)ferrocene palladium dibromide(II), dichloro(N,N,N',N'-tetramethylethylenediamine)palladium(II), bis(triphenylphosphine)palladium chloride, bis(tri-tert-butylphosphine)palladium(O), (R)-1-[(SP)-2-(dicyclohexylphosphino)ferrocene]ethyldi-tert-butylphosphine palladium dichloride(II), bis(tri-tert-butylphosphine)palladium(O), and methane. The following is a list of sulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II), 1,1'-bis(diisopropylphosphino)ferrocene palladium dichloride, dichlorobis(tricyclohexylphosphino)palladium, dichloro(1,1-bis(diphenylphosphino)ferrocene)palladium(II) acetone adduct, bis(tricyclohexylphosphino)palladium dichloride, tetra(triphenylphosphino)palladium, 1,1'-bis(di-cyclohexylphosphino)ferrocene palladium dichloride, and tris(dibenzylideneacetone)palladium(0).

8. The application of the oxyalkylisourea according to claim 5 in introducing methyl groups or isotopically labeled methyl groups in the Suzuki-Miyaura coupling reaction, characterized in that: The alkali is selected from any one of diisopropylamine, N,N-diisopropylethylamine, triethylamine, tripropylamine, tributylamine, N,N-diethylcyclohexylamine, dicyclohexylamine, N-methyldicyclohexylamine, cesium acetate, sodium acetate, magnesium acetate, sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate.

9. The application of the oxyalkylisourea according to claim 5 in introducing methyl groups or isotopically labeled methyl groups in the Suzuki-Miyaura coupling reaction, characterized in that: The amount of the oxyalkylisourea is 1.0 to 5.0 times the molar amount of the arylboride; the amount of the palladium catalyst is 2% to 20% of the molar amount of the arylboride; and the amount of the base is 0.5 to 5.0 times the molar amount of the arylboride.

10. The application of the oxyalkylisourea according to claim 5 in introducing methyl groups or isotopically labeled methyl groups in the Suzuki-Miyaura coupling reaction, characterized in that: The organic solvent B is selected from any one of N,N-dimethylacetamide, N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylpropenylurea, 1,3-dimethyl-2-imidazolinone, tetrahydrofuran, 1,4-dioxane, 1,3-dioxolane, acetonitrile, toluene, methyl tert-butyl ether, cyclopentyl methyl ether, dichloromethane, dichloroethane, diethyl ether, ethyl acetate, and dimethyl sulfoxide.

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