Preparation method and application of deuterated alkyl sulfonium salt reagent

Abstract

The invention discloses a novel preparation method of a deuterated alkyl sulfonium salt reagent, which comprises the following steps: by taking a compound shown in a formula (I) or a compound shown in a formula (II) as a raw material, catalyzing the raw material and a deuterated reagent to perform hydrogen-deuterium exchange reaction by taking alkali metal and / or alkaline earth metal as a catalyst, and then performing cyclization or oxidation and cyclization reaction to prepare deuterated dibenzothiophene onium salt shown in a formula (V), or the compound shown in the formula (III) or the compound shown in the formula (IV) is adopted as a raw material, alkali metal and / or alkaline earth metal are / is adopted as a catalyst to catalyze the hydrogen-deuterium exchange reaction with a deuterated reagent, and then the diaryl sulfonium ether type deuterated salt shown in the formula (VI) or the formula (VII) is prepared through arylation or oxidation and arylation. The method provided by the invention has the advantages of cheap and easily available catalyst, mild reaction conditions, high labeling efficiency and simple process, can synthesize a series of deuterated alkyl sulfonium salt reagents, provides a simple, efficient and economic new strategy for synthesis of deuterated alkyl reagents, and has important scientific significance and industrial application value.

Description

Technical Field

[0001] The invention belongs to the field of chemical synthesis and relates to a new preparation method and application of a deuterated alkyl sulfonium salt reagent. Background Art

[0002] Deuterated organic compounds are compounds formed by replacing one or more hydrogen atoms of an organic compound with its isotope deuterium. In the field of pharmaceutical chemistry, drug deuteration is a commonly used method to change the absorption, distribution, metabolism, and excretion (ADME) process of drug molecules. Due to the better stability of the CD bond, deuterated drugs are metabolized relatively slowly in the body and have a longer half-life, which can reduce the production of toxic metabolites and drug interactions, thereby reducing the dosage, reducing drug side effects, improving safety, and obtaining better efficacy in clinical applications. Therefore, deuterated drug technology is considered to be a simple, efficient, and low-risk drug development model.

[0003] In 2017, the U.S. Food and Drug Administration officially approved Austedo-deuterated tetrabenazine to enter the market, which was the first deuterated drug approved for marketing. In 2021, the deuterated targeted drug Donafenib prepared by Suzhou Zejing Biopharmaceutical Co., Ltd. was also approved for marketing for the treatment of advanced hepatocellular carcinoma. In September 2022, the FDA approved Bristol-Myers Squibb's deuterated oral inhibitor Deucravacitinib for marketing, for the treatment of adult patients with moderate to severe plaque psoriasis who are suitable for systemic treatment or phototherapy. Deuterated drugs are becoming a hot area for new drug research and development.

[0004] During the metabolism of drugs in the body, in the absence of steric hindrance, benzyl, allyl and alkyl carbon-hydrogen bonds adjacent to heteroatoms are ideal substrates for cytochrome metabolizing enzymes and are hot spots for metabolic reactions. Deuteration at these positions can effectively reduce and block the accessibility of metabolic enzymes, thereby effectively slowing down the drug metabolism process. Methyl groups are important building blocks for biologically active molecules and drug molecules. The introduction of methyl groups into drug molecules can effectively improve the solubility of the molecules and the selectivity of the targets. Given the importance of methyl groups in medicinal chemistry, the introduction of deuterated methyl groups into drug molecules will significantly improve the biological processes and drug activity of drug molecules, affect drug efficacy, and play an important role in drug research and development. This is also the reason why the three deuterated drugs on the market all chose deuterated methyl fragments.

[0005] Among the many methods for introducing deuterated methyl groups, deuterated methyl electrophilic reagents are the most commonly used method for the preparation of deuterated methyl modified drugs and natural products; commonly used deuterated methylation reagents include deuterated iodomethane, deuterated dimethyl sulfate, deuterated methyl sulfonate, etc. Although these reagents can be used as synthons for deuterated methyl modified drugs, compounds containing multiple nucleophilic sites often undergo transitional methylation reactions. S-alkylsulfonium salt reagents can be synthesized from alkyl halides and thioethers. They are a widely used class of alkylation reagents with the characteristics of mild conditions, easy operation, and good chemical selectivity. In 2020, Shi Zhuangzhi's team at Nanjing University drew on the structure of Umemoto reagent, synthesized deuterated methyl formate from deuterated methanol, and then reacted with trifluoromethanesulfonic acid and dibenzothiophene to synthesize 5-(deuterated methyl) dibenzothiophenium trifluoromethanesulfonate (DMTT); the reagent can react with different nucleophiles under mild conditions and show excellent chemical selectivity (CN 108658933 A). In this method, the synthesis of sulfonium salt reagents depends on deuterated methanol and deuterated ethanol as raw materials; due to the limitations of deuterated reagent raw materials, this method is difficult to apply to the synthesis of other deuterated alkyl reagents. Under the production demand of deuterated drugs, it is an important trend to develop a new type of deuterated alkyl transfer reagent that is easy to prepare and to achieve selective deuterated alkylation modification of drug molecules and natural products under mild conditions. At present, the synthesis reaction of deuterated alkyl sulfonium salt reagents through hydrogen isotope exchange reaction has not been reported. Summary of the invention

[0006] In order to overcome the problems of complex preparation, poor selectivity, and reagent type limitation of existing deuterated alkyl reagents, the present invention aims to provide a simple, mild, and efficient novel preparation method and application of deuterated alkyl sulfonium salt reagents.

[0007] The present invention provides a novel preparation method of a deuterated alkyl sulfonium salt reagent, wherein the method comprises the following steps: using a compound of formula (I) or a compound of formula (II) as a raw material, catalyzing the compound and a deuterated reagent to undergo a hydrogen-deuterium exchange reaction using an alkali metal and / or an alkaline earth metal as a catalyst, and then subjecting the compound to a cyclization or oxidation / cyclization reaction to obtain a deuterated dibenzothiophenium salt represented by formula (V);

[0008] Alternatively, a deuterated diarylsulfonium salt of formula (VI) or formula (VII) is prepared by using a compound of formula (III) or formula (IV) as a raw material, catalyzing the reaction with a deuterated reagent by using an alkali metal or alkaline earth metal as a catalyst, and then arylating or oxidizing and arylating the compound.

[0009] Wherein, the compound of formula (I) is

[0010] The compound of formula (II) is

[0011] The compound of formula (III) is

[0012] The compound of formula (IV) is

[0013] The compound of formula (V) is

[0014] The compound of formula (VI) is

[0015] The compound of formula (VII) is

[0016] Among them, R1, R2, R3, R4, R5, R6, R7, R8, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 are independently selected from H, methyl, methoxy, trifluoromethyl, phenyl, fluorine, chlorine, bromine, nitro, cyano, etc.; R9 is selected from H, alkyl, benzyl, aryl, etc.; X is selected from O or S.

[0017] Preferably, R1, R2, R3, R4, R5, R6, R7, R8, R 10 , R 11 , R12, R 13 , R 14 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 All are hydrogen.

[0018] In the present invention, the catalyst is selected from any one or more combinations of alkali metals, alkaline earth metal hydroxides, oxides, alcoholates, and hydrides. Preferably, the catalyst is potassium hydroxide.

[0019] in,

[0020] The alkali metal or alkaline earth metal hydroxide is at least one selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, magnesium hydroxide, calcium hydroxide, strontium hydroxide and barium hydroxide.

[0021] And / or, the alkali metal and alkaline earth metal oxide is at least one selected from lithium oxide, sodium oxide, potassium oxide, rubidium oxide, cesium oxide, magnesium oxide, calcium oxide, strontium oxide and barium oxide.

[0022] And / or, the alkali metal or alkaline earth metal alkoxide is selected from at least one of lithium methoxide, lithium ethoxide, lithium isopropoxide, lithium tert-butoxide, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium tert-butoxide, alkoxide rubidium, alkoxide cesium, alkoxide magnesium, alkoxide calcium, alkoxide strontium and alkoxide barium.

[0023] And / or, the alkali metal or alkaline earth metal hydride is at least one selected from lithium hydride, sodium hydride, potassium hydride, rubidium hydride, cesium hydride, magnesium hydride, calcium hydride, strontium hydride and barium hydride.

[0024] In the present invention, the amount of the catalyst used is 1%-150% of the molar amount of the compound of formula (I) or the compound of formula (II) or the compound of formula (III) or the compound of formula (IV); preferably, the amount of the catalyst used is 30% of the molar amount of the compound of formula (I) or the compound of formula (II) or the compound of formula (III) or the compound of formula (IV).

[0025] In the present invention, the deuterated reagent is selected from one or more of heavy water, deuterated dimethyl sulfoxide, deuterated methanol, deuterium gas and the like.

[0026] In the present invention, the reaction is carried out in an organic solvent, and the solvent is any one of aromatic hydrocarbons, alkanes or ether solvents and a combination thereof; preferably, the solvent is n-hexane or benzene.

[0027] In the present invention, the deuterium gas pressure is 1-50 bar; preferably, the deuterium gas pressure is 4 bar.

[0028] In the present invention, the reaction time of the compound of formula (I) or the compound of formula (II) or the compound of formula (III) or the compound of formula (IV) with the deuterated reagent is 12-96 hours; preferably, the reaction time of the compound of formula (I) or the compound of formula (II) or the compound of formula (III) or the compound of formula (IV) with the deuterated reagent is 24 hours.

[0029] In the present invention, the reaction temperature of the compound of formula (I) or the compound of formula (II) or the compound of formula (III) or the compound of formula (IV) and the deuterated reagent is 60° C.-120° C.; preferably, the reaction temperature is 80° C.;

[0030] The temperature for the oxidative cyclization reaction or the reaction with aromatic hydrocarbon after the reaction of the compound of formula (I) or the compound of formula (II) or the compound of formula (III) or the compound of formula (IV) with the deuterated reagent is 0°C-35°C; preferably, the reaction temperature is 25°C.

[0031] In the present invention, the aromatic hydrocarbon is a compound of formula (VIII) Or the aromatic hydrocarbon is a compound of formula (XI)

[0032] Among them, R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 are independently selected from H, methyl, methoxy, trifluoromethyl, phenyl, fluorine, chlorine, bromine, nitro, cyano, etc.; or R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 Any two adjacent ones of the group are bonded to form a ring; X is selected from O or S.

[0033] In the present invention, the oxidative cyclization reaction or the reaction with aromatic hydrocarbons after the reaction of the compound of formula (I) or the compound of formula (II) or the compound of formula (III) or the compound of formula (IV) with the deuterated reagent is carried out in the presence of trifluoromethanesulfonic anhydride; preferably, the molar ratio of the compound of formula (I) or the compound of formula (II) or the compound of formula (III) or the compound of formula (IV) to trifluoromethanesulfonic anhydride is 1:1.5.

[0034] Under preferred conditions, the reaction formula of the preparation method includes but is not limited to one of the following reaction formulas:

[0035] Reaction 1:

[0036]

[0037] Reaction 2:

[0038]

[0039] Reaction three:

[0040]

[0041] Reaction 4:

[0042]

[0043] Reaction 5:

[0044]

[0045] Reaction formula six:

[0046]

[0047] Reaction equation 7:

[0048]

[0049] Reaction formula eight:

[0050]

[0051] Reaction formula 9:

[0052]

[0053] Reaction formula 10:

[0054]

[0055] Reaction formula 11:

[0056]

[0057] The present invention also provides a deuterium-labeled sulfonium salt reagent prepared by the method, namely a deuterated alkyl sulfonium salt reagent, which includes but is not limited to a deuterated dibenzothiophenium salt shown in formula (V), a diaryl sulfonium ether type deuterated salt shown in formula (VI) or formula (VII).

[0058] The present invention also proposes the application of the deuterium-labeled sulfonium salt reagent, including but not limited to application in deuterated alkylation modification of drug molecules, natural products, peptides, proteins and nucleic acids.

[0059] The present invention also proposes the application of the deuterated alkyl sulfonium salt reagent in the preparation of deuterated methyl compounds and deuterated drugs.

[0060] In a specific embodiment, the deuterated alkylsulfonium salt reagent is used for esterification reaction with carboxylic acid, etherification reaction with thiophenol, etherification reaction with phenol, and the like.

[0061] The beneficial effects of the present invention include: the present invention innovatively proposes a preparation method, using alkali metal and / or alkaline earth metal as catalyst, catalyzing the hydrogen-deuterium exchange reaction between the compound of formula (I) or the compound of formula (II) or the compound of formula (III) or the compound of formula (IV) and a deuterated reagent, and synthesizing the deuterated alkyl sulfonium salt reagent through cyclization reaction or reaction with aromatic hydrocarbons. The alkali metal and alkaline earth metal catalysts used in the present invention have the characteristics of abundant reserves, low cost and easy availability; the raw materials used in the present invention are simple, and the deuterated reagent is used as the isotope source to directly prepare the deuterated alkyl sulfonium salt reagent through a "one-pot two-step method", eliminating the traditional multi-step synthesis steps, and the process is simple and suitable for industrial production; the present invention opens up a new green and efficient way for the preparation of new deuterated alkyl sulfonium salt reagents, and has high application value. DETAILED DESCRIPTION

[0062] The invention is further described in detail with reference to the following specific examples. The following specific examples are intended to further illustrate the content of the invention, but not to limit the protection scope of the claims of the invention.

[0063] Example 1: Preparation of 5-(deuterated methyl)dibenzothiophene trifluoromethanesulfonate

[0064] Under inert atmosphere, 2-phenyl-phenylmethyl sulfoxide (CAS: 73475-10-2, 0.3 mmol), benzene (1.0 mL), potassium hydroxide (30 mol%, 0.09 mmol) were added in sequence in a 30 mL autoclave. The autoclave was sealed, filled with 4 bar deuterium gas, and heated at 80°C for 24 hours. The reaction solution was separated by column chromatography to obtain deuterated 2-phenyl-phenylmethyl sulfoxide with a yield of 95%; the product was subjected to nuclear magnetic resonance. 1 HNMR test shows that the deuterium substitution rate is 96%, as shown in the following formula:

[0065]

[0066] 1 H NMR(400MHz, CDCl3)δ8.11(d,J=7.8Hz,1H),7.60(t,J=7.6Hz,1H),7.53(t,J=7.4Hz,1H), 7.48-7.38(m,3H),7.38-7.33(m,2H),7.31(d,J=7.5Hz,1H),2.31(s,0.12H,96%labeled).

[0067] Under inert atmosphere, deuterated 2-phenyl-phenylmethyl sulfoxide (0.1 mmol) and dichloromethane (2.0 mL) were added to a 25 mL Schlenk reaction tube in sequence, and trifluoromethanesulfonic anhydride (150 mol%) was slowly added dropwise at 0°C, and reacted at room temperature for 2 hours. After the reaction was completed, the mixture was filtered through diatomaceous earth, washed with dichloromethane, and the filtrate was concentrated to obtain a white solid product with a yield of 90%. The product was subjected to NMR. 1 H NMR, 13 C NMR test shows that the deuterium substitution rate is 96%, as shown in the following formula:

[0068]

[0069] 1 H NMR (400MHz, CD3CN) δ8.22 (dd, J=20.5, 7.9Hz, 4H), 7.84 (t, J=8.1Hz, 2H), 7.73-7.65 (m, 2H), 3.31 (s, 0.12H, 96% labeled). 13 C NMR(101MHz,CD3CN)δ139.25,133.98,131.07,127.70,124.25,117.47,34.90-33.98(m,labeled,1C).

[0070] Example 2: Preparation of deuterated 2-phenyl-phenylmethyl sulfoxide

[0071] Under inert atmosphere, 2-phenyl-phenylmethyl sulfoxide (CAS: 73475-10-2, 0.3 mmol), deuterated dimethyl sulfoxide (1.0 mL), and potassium hydroxide (30 mol%, 0.09 mmol) were added in sequence to a 25 mL Schlenk reaction tube. The reaction was heated at 80°C for 24 hours. The reaction solution was neutralized, separated, washed with water, dried, concentrated, and separated by column chromatography to obtain deuterated 2-phenyl-phenylmethyl sulfoxide with a yield of 96%. The product was subjected to nuclear magnetic resonance. 1 The deuterium substitution rate was 98% according to H NMR test.

[0072]

[0073] Example 3: Preparation of deuterated 2-phenyl-phenylmethyl sulfoxide

[0074] Under inert atmosphere, 2-phenyl-phenylmethyl sulfoxide (CAS: 73475-10-2, 0.3 mmol), deuterated water (1.0 mL), tetrahydrofuran (1.0 mL), potassium hydroxide (30 mol%, 0.09 mmol) were added in sequence to a 25 mL Schlenk reaction tube. The reaction was heated at 80°C for 24 hours. The reaction solution was neutralized, separated, washed with water, dried, concentrated, and separated by column chromatography to obtain deuterated 2-phenyl-phenylmethyl sulfoxide with a yield of 93%; the product was subjected to nuclear magnetic resonance. 1 The deuterium substitution rate was 94% according to H NMR test.

[0075]

[0076] Example 4: Preparation of 5-(deuterated methyl)dibenzothiophene trifluoromethanesulfonate

[0077] Under inert atmosphere, 2-phenyl-phenyl methyl sulfide (CAS: 19813-75-3, 0.3 mmol), benzene (1.0 mL), and KHMDS (10 mol%) were added in sequence in a 30 mL autoclave. The autoclave was sealed, filled with 4 bar of deuterium gas, and heated at 80°C for 24 hours. The reaction solution was separated by column chromatography to obtain deuterated 2-phenyl-phenyl methyl sulfide with a yield of 94%; the product was subjected to nuclear magnetic resonance. 1 HNMR, 13 C NMR test shows that the deuterium substitution rate is 93%, as shown below:

[0078]

[0079] 1 H NMR (400MHz, CDCl3) δ7.57-7.32(m,7H),7.31-7.23(m,2H),2.53-2.30(m,0.20H,93%labeled). 13 C NMR (101MHz, CDCl3) δ141.1,140.6,137.2,130.1,129.4,128.2,128.0,127.6,125.3,124.8,16.0-15.2(m,labeled,1C).

[0080] Under an inert atmosphere, deuterated 2-phenyl-phenylmethyl sulfide (0.1mmol) and acetic acid (2.0mL) were added to a 25mL Schlenk reaction tube in sequence, and hydrogen peroxide (0.01g) was added dropwise at room temperature, and stirred at room temperature for 12 hours. After the reaction was completed, ethyl acetate was extracted, the organic phase was concentrated, and column chromatography was used to separate a white solid (deuterated 2-phenyl-phenylmethyl sulfoxide) with a yield of 95%. Subsequently, under an inert atmosphere, deuterated 2-phenyl-phenylmethyl sulfoxide (0.1mmol) and dichloromethane (2.0mL) were added to a 25mL Schlenk reaction tube in sequence, and trifluoromethanesulfonic anhydride (150mol%) was slowly added dropwise at 0°C, and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, diatomaceous earth was filtered, washed with dichloromethane, and the filtrate was concentrated to obtain a white solid product with a yield of 88%. The product was subjected to nuclear magnetic resonance. 1 HNMR, 13 C NMR test, as shown below:

[0081]

[0082] 1 H NMR (400MHz,CDCl3) 1 H NMR (400MHz, CD3CN) δ8.22 (dd, J=20.5, 7.9Hz, 4H), 7.84 (t, J=8.1Hz, 2H), 7.73-7.65 (m, 2H), 3.31 (s, 0.20H, 93% labeled). 13 C NMR(101MHz,CD3CN)δ139.25,133.98,131.07,127.70,124.25,117.47,34.90-33.98(m,labeled,1C).

[0083] Example 5: Preparation of deuterated phenyl methyl sulfoxide

[0084] Under inert atmosphere, phenylmethyl sulfoxide (CAS: 1193-82-4, 0.3 mmol), benzene (1.0 mL), and potassium hydroxide (30 mol%) were added in sequence in a 30 mL autoclave. The autoclave was sealed, filled with 4 bar of deuterium gas, and heated at 80°C for 24 hours. The reaction solution was separated by column chromatography to obtain deuterated phenylmethyl sulfoxide with a yield of 96%; the product was subjected to nuclear magnetic resonance. 1 H NMR test shows that the deuterium substitution rate is 93%, as shown in the following formula:

[0085]

[0086] 1H NMR (400MHz, CDCl3) δ7.63 (d, J = 7.1Hz, 2H), 7.56-7.43 (m, 3H), 2.67 (s, 0.20H, 93% labeled).

[0087] Example 6: Preparation of deuterated phenyl methyl sulfoxide

[0088] Under inert atmosphere, phenyl methyl sulfoxide (CAS: 1193-82-4, 0.3 mmol), solvent (1.0 mL), and catalyst (30 mol%) were added in sequence in a 30 mL autoclave. The autoclave was sealed, filled with deuterium gas, and heated for reaction. The reaction solution was separated by column chromatography to obtain deuterated phenyl methyl sulfoxide; the product was subjected to nuclear magnetic resonance. 1 H NMR test, the deuterium substitution rate is shown in the table:

[0089]

[0090]

[0091] Example 7: Preparation of S-(deuterated methyl)diphenylsulfonium ether trifluoromethanesulfonate

[0092] Under an inert atmosphere, deuterated phenylmethyl sulfoxide (0.1 mmol), benzene (0.1 mmol), and dichloromethane (2.0 mL) were added in sequence in a 25 mL Schlenk reaction tube, and trifluoromethanesulfonic anhydride (150 mol%) was slowly added dropwise at 0°C, and reacted at room temperature for 2 hours. After the reaction was completed, the mixture was filtered through diatomaceous earth, washed with dichloromethane, and the filtrate was concentrated to obtain an off-white solid product with a yield of 85%, as shown in the following formula:

[0093]

[0094] 1 H NMR (400MHz, CD3CN) δ7.89-7.53 (m, 10H), 3.53 (s, 0.20H, 93% labeled). 13 CNMR(101MHz,CD3CN)δ134.75,131.60,130.30,126.64,31.26-29.93(m,labeled,1C).

[0095] Example 8: Preparation of S-(deuterated methyl)diphenylsulfonium ether trifluoromethanesulfonate

[0096] Under inert atmosphere, phenyl methyl sulfide (0.3 mmol), deuterated benzene (1.0 mL), and KHMDS (10 mol%) were added in sequence in a 30 mL autoclave. The autoclave was sealed, filled with 4 bar of deuterium gas, and heated at 80°C for 24 hours. The reaction solution was separated by column chromatography to obtain deuterated phenyl methyl sulfide with a yield of 85%; the product was subjected to nuclear magnetic resonance. 1 H NMR, 13 C NMR test shows that the deuterium substitution rate is 97%, as shown in the following formula:

[0097]

[0098] 1 H NMR (400MHz, C6D6) δ7.14-7.06(m,2H),7.05-6.97(m,2H),6.95-6.85(m,1H),2.02-1.85(m,0.08H,97%labeled). 13 C NMR(101MHz,C6D6)δ139.2,129.1,126.9,125.1,15.4-14.5(m,labeled,1C).

[0099] Under an inert atmosphere, deuterated phenyl methyl sulfide (0.1mmol) and acetic acid (2.0mL) were added to a 25mL Schlenk reaction tube in sequence, and hydrogen peroxide (0.01g) was added dropwise at room temperature, and stirred at room temperature for 12 hours. After the reaction was completed, ethyl acetate was extracted, the organic phase was concentrated, and column chromatography was used to separate a white solid (deuterated phenyl methyl sulfoxide) with a yield of 90%. Subsequently, under an inert atmosphere, deuterated phenyl methyl sulfoxide (0.1mmol) and dichloromethane (2.0mL) were added to a 25mL Schlenk reaction tube in sequence, and trifluoromethanesulfonic anhydride (150mol%) was slowly added dropwise at 0°C, and reacted at room temperature for 2 hours. After the reaction was completed, diatomaceous earth was used for filtration, and dichloromethane was used for washing, and the filtrate was concentrated to obtain an off-white solid product with a yield of 80%. The product was subjected to nuclear magnetic resonance. 1 H NMR, 13 C NMR test, as shown below:

[0100]

[0101] 1 H NMR (400MHz, CD3CN) δ7.89-7.53 (m, 10H), 3.53 (s, 0.08H, 97% labeled). 13 CNMR(101MHz,CD3CN)δ134.75,131.60,130.30,126.64,31.26-29.93(m,labeled,1C).

[0102] Embodiment 9:

[0103] Under inert atmosphere, phenylethyl sulfide (0.3mmol), deuterated benzene (0.5mL), and CsHMDS (10mol%) were added in sequence in a 30mL autoclave. The autoclave was sealed, filled with 4bar of deuterium gas, and heated at 80°C for 36 hours. The reaction solution was separated by column chromatography to obtain deuterated phenylethyl sulfide with a yield of 90%; the product was subjected to nuclear magnetic resonance. 1 H NMR, 13 C NMR test shows that the deuterium substitution rate is 99%, as shown in the following formula:

[0104]

[0105] 1 H NMR (400MHz, C6D6) δ7.26-7.19(m,2H),7.05-6.97(m,2H),6.96-6.87(m,1H),2.65-2.47(m,0.02H,99%labeled),1.11-0.97(m,3H). 13 C NMR(101MHz,C6D6)δ137.53,129.28,129.10,125.82,27.45-27.04(m,labeled,1C),14.31.

[0106] Under inert atmosphere, deuterated phenylethyl sulfide (0.1mmol) and acetic acid (2.0mL) were added successively in a 25mL Schlenk reaction tube, and hydrogen peroxide (0.01g) was added dropwise at room temperature, and stirred at room temperature for 12 hours. After the reaction was completed, ethyl acetate was extracted, the organic phase was concentrated, and column chromatography was used to separate a white solid (deuterated phenylethyl sulfoxide) with a yield of 85%. Subsequently, under inert atmosphere, deuterated phenylethyl sulfoxide (0.1mmol) and dichloromethane (2.0mL) were added successively in a 25mL Schlenk reaction tube, and trifluoromethanesulfonic anhydride (150mol%) was slowly added dropwise at 0°C, and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, diatomaceous earth was used for filtration, and dichloromethane was used for washing, and the filtrate was concentrated to obtain the product with a yield of 83%.

[0107]

[0108] Embodiment 10:

[0109] Under an inert atmosphere, deuterated phenylmethyl sulfoxide (Example 5) (0.1 mmol), trimethoxybenzene (0.1 mmol), and dichloromethane (2.0 mL) were added in sequence in a 25 mL Schlenk reaction tube, and trifluoromethanesulfonic anhydride (150 mol%) was slowly added dropwise at 0°C, and reacted at room temperature for 2 hours. After the reaction was completed, the mixture was filtered through diatomaceous earth, washed with dichloromethane, and the filtrate was concentrated to obtain the product with a yield of 85%, as shown in the following formula:

[0110]

[0111] 1 H NMR (400MHz, CDCl3) δ7.46-7.73(m,5H),6.22(s,2H),3.86(s,9H). 13 C NMR (101MHz, CDCl3) δ168.56,162.70,132.67,130.61,126.81,92.49,87.68,56.92,56.40,26.1-25.2(m,labeled,1C).

[0112] Embodiment 11:

[0113] Under an inert atmosphere, deuterated phenylmethyl sulfoxide (Example 5) (0.1 mmol), p-xylene (0.1 mmol), and dichloromethane (2.0 mL) were added in sequence in a 25 mL Schlenk reaction tube, and trifluoromethanesulfonic anhydride (150 mol%) was slowly added dropwise at 0°C, and reacted at room temperature for 2 hours. After the reaction was completed, the mixture was filtered through diatomaceous earth, washed with dichloromethane, and the filtrate was concentrated to obtain the product with a yield of 85%, as shown in the following formula:

[0114]

[0115] 1 H NMR (400MHz, CDCl3) δ7.90-7.80(m,2H),7.76(s,1H),7.61(m,3H),7.36(d,J=7.6, 1H),7.27(t,J=7.2Hz,1H),3.67(s,0.20H,93%labeled),2.49(s,3H),2.43(s,3H). 13 C NMR (101MHz, CDCl3) δ140.07,137.54,135.31,134.10,132.48,131.45,130.00,128.48,126.07,123.47,29.78-29.75(m,labeled,1C),21.04,19.45.

[0116] Embodiment 12:

[0117] Under an inert atmosphere, deuterated phenylmethyl sulfoxide (Example 5) (0.1 mmol), naphthalene (0.1 mmol), and dichloromethane (2.0 mL) were added in sequence in a 25 mL Schlenk reaction tube, and trifluoromethanesulfonic anhydride (150 mol%) was slowly added dropwise at 0°C, and reacted at room temperature for 2 hours. After the reaction was completed, the mixture was filtered through diatomaceous earth, washed with dichloromethane, and the filtrate was concentrated to obtain the product with a yield of 87%, as shown in the following formula:

[0118]

[0119] 1 H NMR(400MHz,CD3CN)δ8.25(t,J=8.9Hz,2H),8.17(d,J=6.8Hz,1H),8.04(d,J=7.6Hz,1H), 7.84(d,J=7.0Hz,2H),7.80–7.61(m,5H),7.59-7.57(m,2H),3.62(s,0.20H,93%labeled). 13 C NMR(101MHz,CD3CN)δ135.21,134.48,131.36,130.12,129.76,129.67,129.42,128.31,126.56,122.18,27.51-26.34(m,labeled,1C).

[0120] Embodiment 13:

[0121] Under an inert atmosphere, deuterated phenylmethyl sulfoxide (0.1 mmol), thiophene (0.1 mmol), and dichloromethane (2.0 mL) were added in sequence in a 25 mL Schlenk reaction tube, and trifluoromethanesulfonic anhydride (150 mol%) was slowly added dropwise at 0°C, and reacted at room temperature for 2 hours. After the reaction was completed, the mixture was filtered through diatomaceous earth, washed with dichloromethane, and the filtrate was concentrated to obtain the product with a yield of 90%, as shown in the following formula:

[0122]

[0123] 1 H NMR (400MHz, CD3CN) δ8.03 (d, J = 24.6Hz, 2H), 7.96-7.77 (m, 2H), 7.77–7.54 (m, 3H), 7.27 (s, 1H), 3.60 (s, 0.20H, 93% labeled). 13C NMR(100MHz,CD3CN)δ138.61,137.84,134.12,130.88,129.00,128.90,31.05-29.76(m,labeled,1C).

[0124] Example 14: Esterification reaction of deuterated alkyl sulfonium salt reagent (deuterated methyl reagent) and carboxylic acid

[0125] Under an inert atmosphere, 5-(deuterated methyl) dibenzothiophene trifluoromethanesulfonate (0.3 mmol), dichloromethane (2 mL), potassium carbonate (0.45 mmol), p-toluic acid (CAS: 99-94-5, 0.3 mmol) were added to a 25 mL Schlenk reaction tube in sequence and reacted at room temperature for 12 hours. After the reaction was completed, a white solid was obtained by column chromatography with a yield of 80%.

[0126]

[0127] 1 H NMR (400MHz, CDCl3) δ7.95 (d, J = 7.6Hz, 2H), 7.25 (d, J = 7.6Hz, 2H), 3.89 (s, 0.2H, 93% labeled), 2.43 (s, 3H). 13 C NMR(100MHz, CDCl3)δ167.21,143.55,129.61,129.07,127.46,51.93-51.22(m,labeled,1C),21.63.

[0128] Example 15: Etherification reaction of deuterated alkyl sulfonium salt reagent (deuterated methyl reagent) and thiophenol

[0129] Under an inert atmosphere, S-(deuterated methyl)phenyl-s-trimethoxyphenylsulfonium ether trifluoromethanesulfonate (0.3mmol), dichloromethane (2mL), cesium carbonate (0.45mmol), p-methylphenylsulfonium phenol (CAS: 106-45-6, 0.3mmol) were added in sequence to a 25mL Schlenk reaction tube, and the reaction was carried out at room temperature for 12 hours. After the reaction was completed, a light yellow liquid was obtained by column chromatography with a yield of 88%.

[0130]

[0131] 1 H NMR (400MHz, CDCl3) δ7.39 (d, J = 7.7Hz, 2H), 7.11 (d, J = 7.7Hz, 2H), 2.49-2.39 (s, 0.20H, 93% labeled). 13C NMR(101MHz, CDCl3)δ131.90,118.71,15.80-15.16(m,labeled,1C).

[0132] Example 16: Etherification reaction of deuterated alkyl sulfonium salt reagent (deuterated methyl reagent) and phenol

[0133] Under an inert atmosphere, S-(deuterated methyl)phenyl-s-trimethoxyphenylsulfonium ether trifluoromethanesulfonate (0.3 mmol), dichloromethane (2 mL), lithium tert-butoxide (0.45 mmol), and p-hydroxybiphenyl (CAS: 92-69-3, 0.3 mmol) were added sequentially to a 25 mL Schlenk reaction tube and reacted at room temperature for 12 hours. After the reaction was completed, a white solid was obtained by column chromatography with a yield of 90%.

[0134]

[0135] 1 H NMR (400MHz, CDCl3) δ7.60 (t, J = 9.0Hz, 4H), 7.47 (t, J = 7.4Hz, 2H), 7.36 (t, J = 7.1Hz, 1H), 7.03 (d, J = 8.3Hz, 2H), 3.90-3.81 (m, 0.20H, 93% labeled). 13 C NMR (100MHz, CDCl3) δ128.74,128.16,126.74,126.67,114.22,55.32-54.56(m,labeled,1C).

[0136] The protection content of the present invention is not limited to the above embodiments. Without departing from the spirit and scope of the present invention, changes and advantages that can be thought of by those skilled in the art are included in the present invention and are protected by the attached claims.

Claims

1. A method for preparing a deuterated alkyl sulfonium salt reagent, characterized in that: The method comprises using a compound of formula (I) or a compound of formula (II) as a raw material, using an alkali metal and / or an alkaline earth metal as a catalyst to catalyze a hydrogen-deuterium exchange reaction between the compound and a deuterated reagent, and then performing a cyclization or oxidation-cyclization reaction to prepare a deuterated dibenzothiophenium salt represented by formula (V); Alternatively, a deuterated diarylsulfonium salt of formula (VI) or formula (VII) is prepared by using a compound of formula (III) or formula (IV) as a raw material, catalyzing it with a deuterated reagent by using an alkali metal and / or an alkaline earth metal as a catalyst, and then arylating or oxidizing and arylating the compound to obtain a deuterated diarylsulfonium salt of formula (VI) or formula (VII); Wherein, the compound of formula (I) is The compound of formula (II) is The compound of formula (III) is The compound of formula (IV) is The compound of formula (V) is The compound of formula (VI) is The compound of formula (VII) is Among them, R1, R2, R3, R4, R5, R6, R7, R8, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 are independently selected from H, methyl, methoxy, trifluoromethyl, phenyl, fluorine, chlorine, bromine, nitro, cyano; R9 is selected from H, alkyl, benzyl, aryl; X is selected from O or S.

2. The preparation method according to claim 1, characterized in that: The alkali metal and alkaline earth metal catalyst is selected from any one or more combinations of alkali metal and alkaline earth metal hydroxides, oxides, alcohol salts, and hydrides; and / or the deuterated reagent is selected from one or more of heavy water, deuterated dimethyl sulfoxide, deuterated methanol, and deuterium gas.

3. The preparation method according to claim 2, characterized in that: The alkali metal or alkaline earth metal hydroxide is at least one selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, magnesium hydroxide, calcium hydroxide, strontium hydroxide and barium hydroxide; And / or, the alkali metal or alkaline earth metal oxide is at least one selected from lithium oxide, sodium oxide, potassium oxide, rubidium oxide, cesium oxide, magnesium oxide, calcium oxide, strontium oxide and barium oxide; and / or, the alkali metal or alkaline earth metal alkoxide is selected from at least one of lithium methoxide, lithium ethoxide, lithium isopropoxide, lithium tert-butoxide, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium isopropoxide, potassium tert-butoxide, alkoxyrubidium, alkoxycesium, alkoxymagnesium, alkoxycalcium, alkoxystrontium and alkoxybarium; And / or, the alkali metal or alkaline earth metal hydride is at least one selected from lithium hydride, sodium hydride, potassium hydride, rubidium hydride, cesium hydride, magnesium hydride, calcium hydride, strontium hydride and barium hydride.

4. The preparation method according to claim 1, characterized in that: The amount of the catalyst used is 1% to 150% of the molar amount of the compound of formula (I), the compound of formula (II), the compound of formula (III), or the compound of formula (IV).

5. The preparation method according to claim 1, characterized in that: The reaction is carried out in an organic solvent, and the solvent is any one of aromatic hydrocarbons, alkanes or ether solvents and a combination thereof.

6. The preparation method according to claim 1, characterized in that: The deuterium gas pressure of the hydrogen-deuterium exchange reaction is 1-50 bar; and / or, The reaction temperature of the compound of formula (I) or the compound of formula (II) or the compound of formula (III) or the compound of formula (IV) and the deuterated reagent is 60° C.-120° C.; The temperature for the oxidative cyclization reaction or the reaction with aromatic hydrocarbon after the compound of formula (I) or the compound of formula (II) or the compound of formula (III) or the compound of formula (IV) reacts with the deuterated reagent is 0°C-35°C; The reaction time of the compound of formula (I) or the compound of formula (II) or the compound of formula (III) or the compound of formula (IV) and the deuterated reagent is 12-96 hours.

7. The preparation method according to claim 1, characterized in that: The aromatic hydrocarbon is a compound of formula (VIII) Or the aromatic hydrocarbon is a compound of formula (XI) Among them, R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 are independently selected from H, methyl, methoxy, trifluoromethyl, phenyl, fluorine, chlorine, bromine, nitro, cyano; or R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 Any two adjacent ones of the group are bonded to form a ring; X is selected from O or S.

8. The preparation method according to claim 1, characterized in that: The cyclization, oxidative cyclization or reaction with aromatic hydrocarbons after the reaction of the compound of formula (I) or the compound of formula (II) or the compound of formula (III) or the compound of formula (IV) with the deuterated reagent is carried out in the presence of trifluoromethanesulfonic anhydride; the molar ratio of the compound of formula (I) or the compound of formula (II) or the compound of formula (III) or the compound of formula (IV) to trifluoromethanesulfonic anhydride is 1:1.

5.

9. A deuterated alkyl sulfonium salt reagent prepared by the method according to any one of claims 1 to 8.

10. Use of the deuterated alkyl sulfonium salt reagent according to claim 9 in the preparation of deuterated methyl compounds and deuterated drugs.

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