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CN-122010656-A - Application of oxyalkylisourea in introducing methyl and isotopically-labeled methyl

CN122010656ACN 122010656 ACN122010656 ACN 122010656ACN-122010656-A

Abstract

The invention discloses an application of oxyalkylisourea in introducing methyl and isotopically labeling methyl. The oxyalkylisourea comprises two applications, namely nucleophilic substitution reaction, namely heating and stirring reaction of oxyalkylisourea and a nucleophilic reagent at 50-130 ℃ under the condition of no addition of any exogenous alkali, so as to obtain a methylation or isotope-labeled methylation product. And secondly, carrying out Suzuki-Miyaura coupling reaction, and stirring and reacting the oxyalkylisourea and the aryl boride at 60-130 ℃ under the action of a palladium catalyst and alkali to obtain a methylation or isotope-labeled methylation product. The methyl of the oxyalkylisourea used in the invention is derived from an inexpensive methanol compound, wherein nucleophilic substitution reaction overcomes the limitation that the existing alkylating reagent must use exogenous alkali, can efficiently introduce methyl and isotope-labeled methyl into drug molecules, realizes the construction of four chemical bonds of C-O, C-S, C-N, C-C, and is easy for large-scale and industrialized application.

Inventors

  • XUE DONG
  • XIONG WEIKANG
  • LI ZHENYU
  • Kang tengfei

Assignees

  • 陕西师范大学

Dates

Publication Date
20260512
Application Date
20260327

Claims (10)

  1. 1. The application of oxyalkylisourea in introducing methyl or isotope labeled methyl in nucleophilic substitution reaction is characterized in that: the structure of the oxyalkylisourea is shown as a formula I: Wherein R 1 represents any one of CH 3 、CD 3 、 13 CH 3 、 13 CD 3 , R 2 and R 3 each 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; Adding oxyalkylisourea shown in a formula I and a nucleophilic reagent shown in a formula II into an organic solvent A, heating and stirring the mixture at 50-130 ℃ under the protection of inert gas and without adding any exogenous alkali, and separating and purifying the mixture after the reaction is finished to obtain a methylated or isotopically labeled methylated product shown in a formula III; The nucleophilic reagent is selected from any one of carboxylic acid compounds, sulfonic acid compounds, phosphoric acid compounds, phenol compounds, mercaptan compounds and amine compounds.
  2. 2. The method for introducing methyl or isotopically-labeled methyl into an oxyalkylisourea in a nucleophilic substitution reaction according to claim 1, wherein the amount of oxyalkylisourea is 2.0-3.0 times the molar amount of a nucleophile.
  3. 3. The use of an oxyalkylisourea according to claim 1 to introduce methyl or isotopically labelled methyl groups in nucleophilic substitution reactions, characterized in that: The carboxylic acid compound is selected from any one of L-methionine, L-cysteine, L-aspartic acid, L-tryptophan, N-t-butoxycarbonyl-L-tryptophan, L-phenylalanine, D-homophenylalanine, L-glutamine, (1S) - (-) -camphoric acid, ursolic acid, lithocholic acid, naproxen, indomethacin, isoxemic acid, clofibrate acid, bezafibrate and febuxostat, or the carboxylic acid compound is selected from a compound with a structural formula of R 4 -COOH, wherein R 4 is phenyl, or R 4 is phenyl substituted by any one or more of C 1 ～C 6 alkyl, C 1 ～C 6 alkoxy, hydroxyl, halogen, cyano, nitro and amino; The structural formula of the sulfonic acid compound is R 5 -SO 3 H, wherein R 5 is selected from any one of phenyl, C 1 ～C 6 alkyl substituted phenyl, naphthyl, C 1 ～C 6 alkyl substituted naphthyl and 5-dimethylamino-1-naphthyl; The structural formula of the phosphoric acid compound is (R 6 O) 2 -P (O) -OH, wherein R 6 is selected from any one of phenyl and C 1 ～C 4 alkyl substituted phenyl; The phenol compound is selected from any one of estrone, coumarin, maltol, vanillin, benzochromone, tribromone and phenolphthalein, or the phenol compound is selected from a compound with a structural formula of R 7 -OH, wherein R 7 is phenyl, or R 7 is phenyl substituted by any one or more of C 1 ～C 6 alkyl, C 1 ～C 6 alkoxy, amino, cyano, halogen and aldehyde benzoyl; The mercaptan compound is selected from any one of 1-thio-B-D-glucose tetraacetate, methimazole, penicillamine and captopril, or the mercaptan compound is selected from a compound with a structural formula of R 8 -SH, wherein R 8 is any one of C 1 ～C 8 alkyl, phenyl and hydroxy-substituted C 3 ～C 10 alkyl, or R 8 is any one or more substituted phenyl groups selected from C 1 ～C 6 alkyl, amino, acetamido, hydroxy, halogen, cyano and nitro; the amine compound is selected from any one of sulfamethoxazole, celecoxib, sulfadiazine sulfanilamide, dimethyl pyrimidine, phthalimide, saccharin, glibenclamide and pioglitazone, or the amine compound is selected from the group consisting of structural formula Wherein R 10 is any one of phenyl, thienyl, halogenated thienyl, or R 10 is phenyl substituted by any one or more of C 1 ～C 6 alkyl, C 1 ～C 6 alkoxy, amino, acetamido, hydroxy, halogen, cyano, nitro.
  4. 4. The application of the oxyalkylisourea in introducing methyl or isotopically labeled methyl in nucleophilic substitution reaction according to claim 1, wherein the organic solvent A is selected from any one of N, N-dimethylacetamide, N-dimethylformamide, N-methylpyrrolidone, N-dimethylpropylurea, tetrahydrofuran, 1, 4-dioxane, 1, 3-dioxolane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, acetonitrile, toluene, methyl tert-butyl ether, cyclopentyl methyl ether, methylene dichloride, dichloroethane, diethyl ether, ethyl acetate and dimethyl sulfoxide.
  5. 5. The application of oxyalkylisourea in introducing methyl or isotope labeled methyl in Suzuki-Miyaura coupling reaction is characterized in that: the structure of the oxyalkylisourea is shown as a formula I: wherein R 1 represents any one of CH 3 、CD 3 、 13 CH 3 or 13 CD 3 , R 2 and R 3 each 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; Adding oxyalkylisourea shown in a formula I, aryl boride, a palladium catalyst and alkali into an organic solvent B, stirring and reacting at 60-130 ℃ under the protection of inert gas, and separating and purifying after the reaction is finished to obtain a methylation or isotope-labeled methylation product; The aryl boride is selected from any one of aryl boric acid, aryl pinacol borate, aryl neopentyl glycol borate and aryl potassium trifluoroborate.
  6. 6. The use of an oxyalkylisourea according to claim 5 for introducing a methyl group or an isotopically labeled methyl group in a Suzuki-Miyaura coupling reaction, wherein the aryl group in the arylboride is selected from any one of phenyl, substituted phenyl, naphthyl, substituted naphthyl, anthracenyl, substituted anthracenyl, pyrenyl, substituted pyrenyl, biphenyl, substituted biphenyl, carbazolyl, substituted carbazolyl, indolyl, substituted indolyl, quinolinyl, substituted quinolinyl, quinoxalinyl, substituted quinoxalinyl, benzoxadiazolyl, substituted benzoxadiazolyl, pyridinyl, substituted pyridinyl; the substitution is substituted by one or more substituents selected from C 1 ～C 4 alkyl, C 1 ～C 4 alkoxy, hydroxymethyl, halogen, cyano, nitro, amino, acetamido, acetoxy, benzoyl, methanesulfonamido and halogenated phenyl; or the aryl boride is selected from 6- (4-BOC-1-piperazino) pyridine-3-boronic acid pinacol ester, N, any one of N-dipropyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzenesulfonamide, isopropyl 2-methyl-2- (4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoyl) phenoxy) propionate or ethyl 2-methyl-2- (4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy) propionate.
  7. 7. The method for preparing a bis (diphenylphosphino) palladium (II) chloride, bis (triphenylphosphine) palladium (0), (R) -1- [ (SP) -2- (dicyclohexylphosphino) ferrocenyl ] ethyl di-tert-butylphosphine palladium (II), bis (tri-tert-butylphosphine) palladium (0), methanesulfonic acid (2-di-tert-butylphosphino-2 ',4',6' -triisopropyl-1, 1' -biphenyl) (2 ' -amino-1, 1' -biphenyl-2-yl) palladium (II), dichloro (N, N, N ', tetramethyl ethylenediamine) palladium (II), bis (triphenylphosphine) palladium chloride, bis (tri-tert-butylphosphine) palladium (0), (R) -1- [ (SP) -2- (dicyclohexylphosphino) ferrocenyl ] ethyl di-tert-butylphosphine palladium (II), bis (tri-tert-butylphosphine) palladium (0), methanesulfonic acid (2-di-tert-butylphosphino-2 ',4',6' -triisopropyl-1, 1' -biphenyl) (2 ' -amino-1, 1' -biphenyl-2-yl) palladium (II), 1' -bis (diisopropylphosphine palladium (dicyclohexyl) ferrocene, 1-dichlorophenyl phosphine (1, 1' -dicyclohexylphosphine) palladium (1, dicyclohexylphosphine) phosphine (1-dicyclohexylphosphine) phosphine, 1-dicyclohexylphosphine (1-diphenylphosphine) phosphine (1-dicyclohexylphosphine) phosphine (1-diphenyl phosphine) phosphine (1-dicyclohexyl phosphine) phosphine (1-diphenyl phosphine) phosphine (ferrocene) phosphine (1-diphenyl phosphine) phosphine Any one of tris (dibenzylideneacetone) dipalladium (0).
  8. 8. The use of an oxyalkylisourea according to claim 5 for introducing methyl or isotopically labeled methyl in a Suzuki-Miyaura coupling reaction, wherein the base is selected from any one of diisopropylamine, N-diisopropylethylamine, triethylamine, tripropylamine, tributylamine, N-diethylcyclohexylamine, dicyclohexylamine, N-methyldicyclohexylamine, cesium acetate, sodium acetate, magnesium acetate, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate.
  9. 9. The application of the oxyalkylisourea in the Suzuki-Miyaura coupling reaction, which is disclosed in claim 5, is characterized in that the oxyalkylisourea is 1.0-5.0 times of the molar amount of aryl boride, the palladium catalyst is 2-20% of the molar amount of aryl boride, and the alkali is 0.5-5.0 times of the molar amount of aryl boride.
  10. 10. The use of an oxyalkylisourea according to claim 5 for introducing methyl or isotopically labeled methyl in a Suzuki-Miyaura coupling reaction, wherein the organic solvent B is selected from any one of N, N-dimethylacetamide, N-dimethylformamide, N-methylpyrrolidone, N-dimethylpropylurea, 1, 3-dimethyl-2-imidazolidinone, tetrahydrofuran, 1, 4-dioxane, 1, 3-dioxolane, acetonitrile, toluene, methyl tert-butyl ether, cyclopentyl methyl ether, methylene chloride, dichloroethane, diethyl ether, ethyl acetate, dimethyl sulfoxide.

Description

Application of oxyalkylisourea in introducing methyl and isotopically-labeled methyl Technical Field The invention belongs to the technical field of organic synthesis, and particularly relates to application of oxyalkylisourea in introducing methyl and isotopically-labeled methyl, in particular to a method for efficiently introducing methyl, deuterated methyl, 13 C-labeled methyl and 13 C-labeled deuterated methyl into an organic compound by nucleophilic substitution reaction under the condition of no exogenous alkali and by Suzuki-Miyaura coupling reaction under the catalysis of palladium. Background The introduction of methyl into drug molecules can produce favorable desolvation energy effects, regulate metabolic stability, precisely regulate hydrophobic interactions and induce conformational changes, thereby significantly improving the activity and solubility of the drug, and the 'magic methyl effect' is widely focused in the field of pharmaceutical chemistry. On the basis, the hydrogen atoms in the methyl are replaced by stable isotopes (deuterium or 13 C), and the fluorescent dye can be used as a non-radioactive tracer for researching the metabolic process of drug molecules, realizing higher marking depth, simultaneously exploring a plurality of metabolic pathways and maximizing the information acquisition amount of a single experiment. For example, drugs Austedo (deutetrabenazine) for treating Huntington's disease and glipizide as hypoglycemic agents, namely, dynamic isotope effects generated by replacing hydrogen atoms with deuterium atoms are utilized to effectively reduce the metabolic degradation rate, so that the dosage advantage is obtained, and 13 C-labeled riboflavin and 13 C/deutetrabecan double-labeled apixaban are widely applied to metabolic research and quantitative analysis. Therefore, the development of an efficient and mild method introduces the stable isotope labeled methyl into the drug molecules, and has important scientific significance and application value. 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. Among them, CD 3I、CD3 OD and (CD 3)2SO4 are the most commonly used deuterated methyl sources in synthetic chemistry, but they have problems of volatility, corrosiveness, toxicity, carcinogenicity, etc., in view of the above problems, researchers have developed a variety of novel methylating agents in recent years, but the prior art has limitations. CN117946067B discloses a method for realizing deuteration methylation of nucleophile, which adopts thianthrene onium salt deuteration methylation reagent (5-deuteration methyl-5H-thiophene-5-onium triflate), and reacts with nucleophile under alkaline condition to realize deuteration methylation. The technical scheme can realize deuteration methylation of a nucleophilic reagent, but has the following problems that firstly, exogenous alkali (such as triethylamine) is required to be added for the reaction, the reaction is inapplicable to acid-base sensitive substrates, and side reactions can be caused by the added alkali, secondly, the adopted thianthrene onium salt reagent is complex in synthesis steps, multi-step reaction preparation is required, the cost is high, thirdly, the reagent is only suitable for introducing deuterated methyl, 13 C marked methyl and other isotope marked forms are not involved, and fourthly, the reagent can only realize construction of C-S, C-N, C-O bonds and cannot be used for construction of C-C bonds. It is noted that all nucleophilic substitution methylation reactions in the prior art rely on the participation of exogenous base, and when reacting with carboxylic acids, phenols, thiols, sulfonamides and sulfonic acids without exogenous base, it is difficult to obtain the corresponding methylation products. CN120923407a discloses a method for synthesizing oxyalkylisourea and its use as a free radical alkylating agent. According to the technical scheme, an alcohol compound and carbodiimide are used as raw materials, oxyalkylisourea is synthesized under metal catalysis, and is used as a free radical alkylating reagent to be applied to a nickel-catalyzed coupling reaction, and the preparation of an alkylation product is realized through a single electron transfer process. However, the technical scheme has the following problems that firstly, the oxyalkylisourea only takes part in the reaction as a free radical precursor, the reaction mechanism is free radical cross-coupling, but is not electrophilic two-electron nucleophilic substitution reaction, secondly, the technical scheme does not relate to the application of the oxyalkylisourea in nucleophilic substitution reaction and the introduction of methyl or isotope-labeled methyl, thirdly, a nickel catalytic system adopted by the technical scheme needs to be added with a ligand and alkali, an