Synthesis method and application of electrophilic selenium deuterated methyl reagent

Abstract

The invention discloses a synthesis method and application of an electrophilic selenium deuterated methyl reagent. The method comprises the following steps: firstly, adding sodium p-toluenesulfinate and selenium powder into a drying container in a nitrogen environment, adding D3-methyl p-toluenesulfonyl ester and an organic solvent in a sealed state, carrying out stirring reaction at normal temperature, extracting a product, drying, filtering, carrying out rotary evaporation to remove the solvent, and carrying out silica gel column chromatography to obtain the selenium deuterated methyl reagent. The reagent is used for preparing trideuterated methyl selenide alkyl ether, trideuterated methyl selenide alkynyl ether or trideuterated methyl selenide aryl ether. According to the method disclosed by the invention, the selenium deuterated methyl reagent can be obtained under the conditions of normal temperature and no additional additive by taking the deuterated methanol which is cheap and easy to obtain as an initial substance, and the cost is low. The electrophilic selenium deuterated methyl reagent prepared by the method disclosed by the invention reacts with beta-ketone ester, a terminal alkyne derivative, arylboronic acid or an arylboronic acid pinacol ester substrate, so that the construction of C (sp2)-SeCD3 and C (sp3)-SeCD3 bonds is realized.

Description

Technical Field

[0001] The invention belongs to the technical field of chemistry, and relates to a synthesis method and application of an electrophilic selenodeuterated methyl reagent, which is applied to react with different electrophilic reagents and nucleophilic reagents under different conditions to prepare a selenodeuterated methyl product. Background Art

[0002] Selenium is an essential trace element for humans and animals. It is of great significance to maintain human health, especially in the metabolism of thyroid hormones. Due to its large atomic radius, selenium atoms may increase the steric hindrance of drugs when introduced into drug molecules, thereby affecting the efficacy of drugs. In addition, selenium has the characteristics of low polarity and easy polarization, which makes selenium-containing drugs generally show stronger lipid solubility and better cell membrane permeability. These unique properties make selenium show a wide range of application prospects in the field of medicinal chemistry, providing an important innovative direction for the design and development of new drugs.

[0003] Deuterium atoms, as the biological electronic isostere of hydrogen atoms, are well known to chemists for their wide application in drug discovery and development. Deuterium atoms have many characteristics compared to hydrogen atoms, such as shorter CD bond length, lower vibration frequency, and higher dissociation energy than CH bonds, which can directly affect the absorption, distribution, metabolism and excretion of certain drug molecules, thereby improving the effectiveness, tolerance and safety of drugs. Therefore, deuterium atoms make minor modifications to hydrogen-containing drug molecules to extend the half-life of drugs, reduce drug toxicity, enhance drug absorption and metabolism, and enhance the desired biological drugs or physical properties without changing the original drug's advantageous effects.

[0004] Selenodeuterated methyl (SeCD 3 ) has gradually attracted attention in chemical research and application in recent years. However, the research on selenodeuterated methyl is still in a relatively preliminary stage and has not been widely reported. The preparation of such compounds faces many technical difficulties, especially how to ensure the deuteration rate (>99%) reaches an ideal level while achieving high yield, which has become a major challenge in this field.

[0005] At present, the development and application of electrophilic selenodeuterated methyl reagents are mostly prepared by deuterated dimethyl sulfoxide, which requires about 40 equivalents of deuterated dimethyl sulfoxide, which is costly, and the deuteration rate can only reach 91%. In addition, there are few examples of direct introduction of selenodeuterated methyl in the future, and the deuteration rate of the product can only reach 91%, which cannot meet the subsequent research and development needs of related selenium-containing deuterated drugs. Therefore, it is of great significance to select a cheap and easily available deuterium source as the starting material, develop a new method for synthesizing electrophilic selenodeuterated methyl reagents with high activity, high deuteration rate and adjustable structure, and at the same time study and expand this compound in the efficient direct introduction of selenodeuterated groups. Summary of the invention

[0006] One object of the present invention is to provide a method for synthesizing an electrophilic selenodeuterated methyl reagent. The electrophilic selenodeuterated methyl reagent is selenium-(methyl-d 3 ) p-Toluenesulfonate selenoester.

[0007] The method of the present invention is specifically as follows:

[0008] Step (1) placing the container in an oven for drying, placing a magnet in the container after drying, pumping air under a nitrogen atmosphere to ensure that the container is in a nitrogen environment, and cooling to room temperature; the drying temperature is 80° C. to 150° C., and the drying time is 1 to 3 hours; pumping air 2 to 4 times to achieve a nitrogen environment;

[0009] Step (2) adding sodium p-toluenesulfinate and selenium powder in a molar ratio of 1:1 into the container, pumping and exchanging air under a nitrogen atmosphere to ensure that the container is a nitrogen environment, and then sealing the container; pumping and exchanging air 2 to 4 times to achieve a nitrogen environment;

[0010] Step (3) Add D in a sealed state 3 - p-Toluenesulfonyl methyl ester and organic solvent, D 3 - the molar ratio of p-toluenesulfonyl methyl ester to sodium p-toluenesulfinate is (0.75-0.95):1, and 1.5-2.5 ml of an organic solvent is added per millimole of sodium toluenesulfinate; the organic solvent is N,N-dimethylformamide solvent or N,N-dimethylacetamide solvent;

[0011] Step (4) is stirred and reacted at room temperature for 18 to 30 hours, and the reaction formula is as follows:

[0012]

[0013] After the reaction in step (5) is completed, the reaction solution is poured into water, the organic phase is extracted with ethyl acetate 2 to 3 times, and the organic phases are combined; back-extracted with water 3 to 6 times, and then dried with anhydrous sodium sulfate, filtered and evaporated to remove the solvent; the crude product is chromatographed on a silica gel column to obtain selenium-(methyl-d 3 ) p-Toluenesulfonate selenoester.

[0014] The method of the invention overcomes the shortcomings of expensive starting materials, complicated reagent synthesis and low reagent activity in previous methods. The method uses cheap and easily available deuterated methanol as an initial material and starts from 1 equivalent of deuterated methanol. After two steps of reaction, the selenium deuterated methyl reagent can be obtained by column chromatography separation at room temperature without adding any external additives, and the cost is low.

[0015] Another object of the present invention is to provide an application of the electrophilic deuterated selenide methyl reagent prepared by the above method as a preparation of trideuterated methyl selenoether.

[0016] Furthermore, the trideuterated methylselenoether is trideuterated methylselenoalkyl ether, and the applied substrate is β-ketoester.

[0017] Furthermore, the trideuterated methylselenoether is trideuterated methylselenoynyl ether, and the applied substrate is a terminal alkyne derivative.

[0018] Furthermore, the trideuterated methyl selenide is trideuterated methyl selenide aryl ether, and the applied substrate is aryl boronic acid or aryl boronic acid pinacol ester.

[0019] The electrophilic selenodeuterated methyl reagent prepared by the method of the present invention reacts with a β-keto acid ester, a terminal alkyne derivative, an aryl boronic acid or an aryl boronic acid pinacol ester substrate to achieve C(sp 2 )-SeCD 3 、C(sp 3 )-SeCD 3 Key construction. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 The hydrogen nuclear magnetic resonance spectrum of the product of one embodiment of the present invention;

[0021] Figure 2 The carbon nuclear magnetic resonance spectrum of the product of one embodiment of the present invention is shown in FIG. DETAILED DESCRIPTION

[0022] The preparation method and specific application of the present invention are further described below in conjunction with specific examples, but the following examples are by no means limiting the present invention in any way.

[0023] First, the existing method (patent number: 201110064696.0) was used to synthesize D using deuterated methanol as a deuterium source. 3 -p-Toluenesulfonyl methyl ester, and then prepare selenium-(methyl-d 3 ) p-Toluenesulfonate selenoester.

[0024] Preparation Example 1.

[0025] Step (1) placing a 200 mL round-bottom flask in an oven at 120° C. for 2 hours, placing a magnet in the container after drying, evacuating and exchanging air three times under a nitrogen atmosphere to ensure that the container is in a nitrogen environment, and cooling to room temperature;

[0026] Step (2) Add 33.0 mmol sodium p-toluenesulfinate and 33.0 mmol selenium powder into a container and ventilate the container three times under a nitrogen atmosphere, then seal the container;

[0027] Step (3) Add 30.0 mmol of D 3 - p-Toluenesulfonyl methyl ester and 60.0 mL of ultra-dry N,N-dimethylformamide;

[0028] Step (4) was stirred at 22° C. for 24 hours. The reaction formula was as follows:

[0029]

[0030] After the reaction of step (5) is completed, the reaction solution is poured into water, the organic phase is extracted with ethyl acetate (50.0 mL×3), and the organic phases are combined; back-extracted with water 5 times, then dried over anhydrous sodium sulfate, filtered and evaporated to remove the solvent; the crude product is chromatographed on a silica gel column to obtain a yellow solid target product with an isolation yield of 58% and a deuteration rate of 99.9%.

[0031] The obtained selenium-(methyl-d 3 ) p-Toluenesulfonate selenoester: melting point = 39.1–40.0°C. 1 H NMR (400 MHz, CDCl 3 ) δ7.76 (d, 2H, J = 8.4Hz), 7.34 (2H, d, J = 8.1Hz), 2.45 (3H, s). 13 C NMR (101 MHz, CDCl 3 )δ144.78, 143.62, 129.83, 126.56, 12.8–12.1 (m, CD 3 ).

[0032] Preparation Example 2.

[0033] Step (1) placing a 300 mL round-bottom flask in a 150° C. oven for 1 hour, placing a magnet in the container after drying, evacuating and exchanging air three times under a nitrogen atmosphere to ensure that the container is in a nitrogen environment, and cooling to room temperature;

[0034] Step (2) Add 50.0 mmol sodium p-toluenesulfinate and 50.0 mmol selenium powder into the container and ventilate it 4 times under nitrogen atmosphere, then seal the container;

[0035] Step (3) Add 37.5 mmol of D 3 - p-Toluenesulfonyl methyl ester and 75.0 mL of N,N-dimethylacetamide;

[0036] Step (4) The reaction was stirred at 20° C. for 30 hours. The reaction formula is as follows:

[0037]

[0038] Step (5) After the reaction was completed, the reaction solution was poured into water, the organic phase was extracted with ethyl acetate (50.0 mL × 2), and the organic phases were combined; back-extracted with water for 6 times, then dried over anhydrous sodium sulfate, filtered and evaporated to remove the solvent; the crude product was subjected to silica gel column chromatography to obtain the yellow solid target product (selenium-(methyl-d3 ) p-Toluenesulfonate selenoester), deuteration rate 99.8%.

[0039] Preparation Example 3.

[0040] Step (1) placing a 500 mL round-bottom flask in an oven at 125° C. for 1.5 hours, placing a magnet in the container after drying, evacuating the container 4 times under a nitrogen atmosphere to ensure that the container is in a nitrogen environment, and cooling the container to room temperature;

[0041] Step (2) Add 50.0 mmol sodium p-toluenesulfinate and 50.0 mmol selenium powder into a container and ventilate twice under a nitrogen atmosphere, then seal the container;

[0042] Step (3) Add 47.5 mmol of D 3 - p-Toluenesulfonyl methyl ester and 125.0 mL of N,N-dimethylacetamide;

[0043] Step (4) was stirred at 25° C. for 18 hours. The reaction formula is as follows:

[0044]

[0045] Step (5) After the reaction was completed, the reaction solution was poured into water, the organic phase was extracted with ethyl acetate (50.0 mL × 3), and the organic phases were combined; back-extracted with water 3 times, then dried over anhydrous sodium sulfate, filtered and evaporated to remove the solvent; the crude product was subjected to silica gel column chromatography to obtain the yellow solid target product (selenium-(methyl-d 3 ) p-Toluenesulfonate selenoester), deuteration rate 99.6%.

[0046] Preparation Example 4.

[0047] Step (1) placing a 500 mL round-bottom flask in an oven at 80° C. for 3 hours, placing a magnet in the container after drying, evacuating the container twice under a nitrogen atmosphere to ensure that the container is in a nitrogen environment, and cooling the container to room temperature;

[0048] Step (2) Add 50.0 mmol sodium p-toluenesulfinate and 50.0 mmol selenium powder into the container and ventilate the container three times under nitrogen atmosphere, then seal the container;

[0049] Step (3) Add 42.5 mmol of D 3 - p-Toluenesulfonyl methyl ester and 100.0 mL of N,N-dimethylformamide;

[0050] Step (4) The reaction was stirred at 23° C. for 20 hours. The reaction formula is as follows:

[0051]

[0052] Step (5) After the reaction was completed, the reaction solution was poured into water, the organic phase was extracted with ethyl acetate (50.0 mL × 2), and the organic phases were combined; back-extracted with water 4 times, then dried over anhydrous sodium sulfate, filtered and evaporated to remove the solvent; the crude product was subjected to silica gel column chromatography to obtain the yellow solid target product (selenium-(methyl-d 3 ) p-Toluenesulfonate selenoester), deuteration rate 99.4%.

[0053] Application Example 1.

[0054]

[0055] Specific operation steps: Place a 25.0 mL sealed tube in a 120°C oven for 1-2 hours, place a magnetic bar, cool to room temperature, evacuate 3 times under a nitrogen atmosphere, add 0.5 mmol of 1H-indene-2-carboxylic acid, 2,3-dihydro-1-oxo-, methyl ester, 1.0 mmol of deuterated reagent and 1.0 mmol of potassium carbonate, evacuate 3 times under a nitrogen atmosphere, add 2.5 mL of ultra-dry dichloromethane, stir and react at 35°C for 12 hours, pour the reaction solution into 20.0 mL of water, extract the organic phase with dichloromethane (30.0 mL×3), combine the organic phases and back-extract with water 3 times, then dry with anhydrous sodium sulfate for 15 minutes, filter with a sand core funnel, combine the organic phases, and remove the solvent by rotary evaporation. Finally, the crude product can be separated by silica gel column chromatography to obtain a colorless oily liquid target product with a separation yield of 95%, and the deuteration rate is>99%. 1 H NMR (400 MHz, CDCl 3 ) δ7.79 (1H, d, J = 7.5Hz), 7.59 (1H, dd, J = 7.5, 7.4Hz), 7.41–7.38 (2H, m), 3.97 (1H, d, J = 18.3Hz), 3.79 (3H, s), 3.15 (1H, d, J = 18.3Hz); 13 C NMR (101 MHz, CDCl 3 )δ196.2, 170.2, 149.6, 135.2, 133.9, 128.2, 126.1, 125.4, 53.3, 49.6, 39.0, 6.4–5.5 (m, CD 3 ); HRMS(ESI + )[M+H] + Calculated value C 12 H 10 D 3 O 3 Se: 282.0272, measured value: 282.0278.

[0056] Application Example 2.

[0057]

[0058] Specific operation steps: Place the 25.0mL sealed tube in a 120℃ oven for 1-2 hours, put in a magnetic bar, cool to room temperature, evacuate 3 times under nitrogen atmosphere, add 0.5mmol of 5-chloro-1-oxo-2,3-dihydro-1H-indene-2-carboxylic acid methyl ester, 1.0mmol of deuterated reagent and 1.0mmol of potassium carbonate, evacuate 3 times under nitrogen atmosphere, add 2.5mL of ultra-dry dichloromethane, stir and react at 35℃ for 12h, pour the reaction solution into 20.0mL of water, extract the organic phase with dichloromethane (30.0mL×3), combine the organic phases and back-extract with water 3 times, then dry with anhydrous sodium sulfate for 15min, filter with a sand core funnel, combine the organic phases, and remove the solvent by rotary evaporation. Finally, the crude product can be separated by silica gel column chromatography to obtain the yellow solid target product with an isolation yield of 86%, and the deuteration rate is>99%. Melting point = 96.9–97.7℃; 1 H NMR (400 MHz, CDCl 3 ) δ7.69 (1H, d, J = 8.1Hz), 7.47–7.27 (2H, m), 3.94 (1H, d, J = 18.5Hz), 3.78 (3H, s), 3.09 (1H, d, J = 18.5Hz); 13 CNMR (101MHz, CDCl 3 )δ194.5, 169.8, 150.9, 141.6, 132.4, 128.9, 126.4, 126.3, 53.3, 49.3, 38.5, 6.6–5.7 (m, CD 3 ); HRMS(ESI + )[M+H] + Calculated value C 12 H 9 D 3 C1O 3 Se: 315.9883, measured value: 315.9882.

[0059] Application Example 3.

[0060]

[0061] Specific operation steps: Place the 25.0mL sealed tube in a 120℃ oven for 1-2 hours, put in a magnetic bar, cool to room temperature, evacuate 3 times under nitrogen atmosphere, add 0.5mmol of 5-bromo-1-oxo-2,3-dihydro-1H-indene-2-carboxylic acid methyl ester, 1.0mmol of deuterated reagent and 1.0mmol of potassium carbonate, evacuate 3 times under nitrogen atmosphere, add 2.5mL of ultra-dry dichloromethane, stir and react at 35℃ for 12h, pour the reaction solution into 20.0mL of water, extract the organic phase with dichloromethane (30.0mL×3), combine the organic phases and back-extract with water 3 times, then dry with anhydrous sodium sulfate for 15min, filter with a sand core funnel, combine the organic phases, and remove the solvent by rotary evaporation. Finally, the crude product can be separated by silica gel column chromatography to obtain the yellow solid target product with a separation yield of 99%, and the deuteration rate is>99%. Melting point = 83.2–83.7℃; 1 H NMR (400 MHz, CDCl 3 ) δ7.63 (1H, d, J = 8.1Hz), 7.57 (1H, s), 7.52 (1H, d, J = 8.6Hz), 3.95 (1H, d, J = 18.4Hz), 3.79 (3H, s), 3.10 (1H, d, J = 18.5Hz); 13 C NMR (101 MHz, CDCl 3 )δ194.7, 169.8, 151.0, 132.8, 131.8, 130.5, 129.4, 126.5, 53.4, 49.2, 38.4, 6.6–5.8 (m, CD 3 ); HRMS(ESI + )[M+H] + Calculated value C 12 H 9 D 3 B O 3 Se: 359.9377, measured value: 359.9369.

[0062] Application Example 4.

[0063]

[0064] Specific operation steps: Place 25.0mL sealed tube in a 120℃ oven for 1-2 hours, put in a magnetic bar, cool to room temperature, evacuate 3 times under nitrogen atmosphere, add 0.5mmol of 1-oxo-2,3-dihydro-1H-indene-2-carboxylic acid ethyl ester, 1.0mmol deuterated reagent and 1.0mmol potassium carbonate, evacuate 3 times under nitrogen atmosphere, add 2.5mL ultra-dry dichloromethane, stir and react at 35℃ for 12h, pour the reaction solution into 20.0mL of water, extract the organic phase with dichloromethane (30.0mL×3), combine the organic phases and back-extract with water 3 times, then dry with anhydrous sodium sulfate for 15min, filter with a sand core funnel, combine the organic phases, and remove the solvent by rotary evaporation. Finally, the crude product can be separated by silica gel column chromatography to obtain the target product in a yellow oily liquid with a separation yield of 98%, and the deuteration rate is>99%. 1 H NMR (500 MHz, CDCl 3 )δ7.77(1H, d, J=7.6Hz), 7.57(1H, dd, J=7.6, 7.4Hz), 7.37(2H, d, J=8.6Hz), 4.27– 4.20 (2H, m), 3.96 (1H, d, J = 18.2Hz), 3.12 (1H, d, J = 18.2Hz), 1.27 (3H, t, J = 7.1Hz); 13 C NMR (126 MHz, CDCl 3 )δ196.1, 169.5, 149.5, 135.0, 133.9, 128.0, 126.0, 125.1, 62.2, 49.5, 38.8, 14.0, 6.1–5.4 (m, C-D3); HRMS (ESI + )[M+H] + Calculated value C 13 H 12 D 3 O 3 Se: 296.0429, measured value: 296.0423.

[0065] Application Example 5.

[0066]

[0067] Specific operation steps: Place a 25.0 mL sealed tube in an oven at 120°C for 1-2 hours, place a magnetic bar, cool to room temperature, evacuate 3 times under a nitrogen atmosphere, add 0.5 mmol of 1,1-dimethylethyl 2,3-dihydro-1-oxo-1H-indene-2-carboxylate, 1.0 mmol of a deuterated reagent and 1.0 mmol of potassium carbonate, evacuate 3 times under a nitrogen atmosphere, add 2.5 mL of ultra-dry dichloromethane, stir and react at 35°C for 12 hours, pour the reaction solution into 20.0 mL of water, extract the organic phase with dichloromethane (30.0 mL×3), combine the organic phases and back-extract with water 3 times, then dry with anhydrous sodium sulfate for 15 minutes, filter with a sand core funnel, combine the organic phases, and remove the solvent by rotary evaporation. Finally, the crude product can be separated by silica gel column chromatography to obtain a yellow oily liquid target product with a separation yield of 94%, and the deuteration rate is >99%. 1 H NMR (400 MHz, CDCl 3 ) δ7.78 (1H, d, J = 7.5Hz), 7.58 (1H, dd, J = 7.7, 7.2Hz), 7.40–7.37 (2H, m), 3.92 (1H, d, J = 18.3Hz), 3.10 (1H, d, J = 18.3Hz), 1.47 (9H, s); 13 C NMR (101 MHz, CDCl 3 )δ196.6, 168.6, 149.7, 135.0, 134.2, 128.0, 126.1, 125.2, 82.9, 50.5, 39.0, 28.0, 6.2–5.3 (m, CD 3 ); HRMS(ESI + )[M+H] + Calculated value C 15 H 16 D 3 O 3 Se: 324.0742, measured value: 324.0750.

[0068] Application Example 6.

[0069]

[0070] Specific operation steps: Place a 25.0mL sealed tube in an oven at 120°C for 1-2 hours, place a magnetic bar, cool to room temperature, ventilate 3 times under a nitrogen atmosphere, add 0.5mmol phenylacetylene, 0.75mmol deuterated reagent, 0.025mmol cuprous iodide, 0.03mmol 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene and 0.75mmol potassium carbonate, ventilate 3 times under a nitrogen atmosphere, add 5.0mL ultra-dry dimethyl sulfoxide, stir and react at 22°C for 24h, pour the reaction solution into 25.0mL water, extract the organic phase with dichloromethane (30.0mL×3), combine the organic phases and back-extract with water 3 times, then dry with anhydrous sodium sulfate for 15min, filter with a sand core funnel, combine the organic phases, and remove the solvent by rotary evaporation. Finally, the crude product can be separated by silica gel column chromatography to obtain a yellow oily liquid target product with a separation yield of 85%, and the deuteration rate is >99%. 1 H NMR (400 MHz, CDCl 3 )δ7.44–7.43(2H, m), 7.33–7.30(3H, m); 13 C NMR (101 MHz, CDCl 3 )δ131.6, 128.4, 128.2, 123.6, 98.3, 71.3, 9.7–9.0 (m, CD 3 ); HRMS(APCI + )[M+Na] + Calculated value C 9 H 5 D 3 NaSe: 215.9931, measured value: 215.9925.

[0071] Application Example 7.

[0072]

[0073] Specific operation steps: place a 25.0 mL sealed tube in an oven at 120°C for 1-2 hours, put in a magnetic bar, cool to room temperature, ventilate 3 times under a nitrogen atmosphere, add 0.5 mmol of 4-bromophenylacetylene, 0.75 mmol of deuterated reagent, 0.025 mmol of cuprous iodide, 0.03 mmol of 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene and 0.75 mmol of potassium carbonate, ventilate 3 times under a nitrogen atmosphere, add 5.0 mL of ultra-dry dimethyl sulfoxide, stir and react at 22°C for 24 hours, pour the reaction solution into 25.0 mL of water, extract the organic phase with dichloromethane (30.0 mL×3), combine the organic phases and back-extract with water 3 times, then dry with anhydrous sodium sulfate for 15 minutes, filter with a sand core funnel, combine the organic phases, and remove the solvent by rotary evaporation. Finally, the crude product was separated by silica gel column chromatography to obtain the target product in a yellow oily liquid with a separation yield of 76%, and the deuteration rate was >99%. 1 H NMR (400 MHz, CDCl 3 )

[0074] δ7.42 (2H, dd, J=8.4, 1.5Hz), 7.26 (2H, dd, J=8.4, 1.5Hz); 13 C NMR (101 MHz, CDCl 3 )

[0075] δ133.0, 131.6, 122.5, 122.3, 97.2, 73.0, 9.8–8.9 (m, CD 3 ); HRMS(APCI + )[M+Na] + Calculated value C 9 H 4 D 3 BrNaSe: 293.9036, measured value: 293.9039.

[0076] Application Example 8.

[0077]

[0078] Specific operation steps: place a 25.0 mL sealed tube in an oven at 120°C for 1-2 hours, put in a magnetic bar, cool to room temperature, ventilate 3 times under a nitrogen atmosphere, add 0.5 mmol of methyl 4-ethynylbenzoate, 0.75 mmol of deuterated reagent, 0.025 mmol of cuprous iodide, 0.03 mmol of 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene and 0.75 mmol of potassium carbonate, ventilate 3 times under a nitrogen atmosphere, add 5.0 mL of ultra-dry dimethyl sulfoxide, stir and react at 22°C for 24 hours, pour the reaction solution into 25.0 mL of water, extract the organic phase with dichloromethane (30.0 mL×3), combine the organic phases and back-extract with water 3 times, then dry with anhydrous sodium sulfate for 15 minutes, filter with a sand core funnel, combine the organic phases, and remove the solvent by rotary evaporation. Finally, the crude product can be separated by silica gel column chromatography to obtain a colorless oily liquid target product with a separation yield of 82%, and the deuteration rate is >99%. 1 HNMR (400 MHz, CDCl 3 ) δ7.94 (2H, d, J = 8.4Hz), 7.43 (2H, d, J = 8.5Hz), 3.88 (3H, s); 13 CNMR (101MHz, CDCl 3 )δ166.5, 131.1, 129.5, 129.2, 128.2, 97.9, 75.7, 52.2, 9.8–9.1 (m, CD 3 ); HRMS(APCI + )[M+H] + Calculated value C 11 H 8 D 3 O 2 Se: 252.0167, measured value: 252.0176.

[0079] Application Example 9.

[0080]

[0081] Specific operation steps: place a 25.0 mL sealed tube in an oven at 120°C for 1-2 hours, put in a magnetic bar, cool to room temperature, ventilate 3 times under a nitrogen atmosphere, add 0.5 mmol of 2-naphthylacetylene, 0.75 mmol of deuterated reagent, 0.025 mmol of cuprous iodide, 0.03 mmol of 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene and 0.75 mmol of potassium carbonate, ventilate 3 times under a nitrogen atmosphere, add 5.0 mL of ultra-dry dimethyl sulfoxide, stir and react at 22°C for 24 hours, pour the reaction solution into 25.0 mL of water, extract the organic phase with dichloromethane (30.0 mL×3), combine the organic phases and back-extract with water 3 times, then dry with anhydrous sodium sulfate for 15 minutes, filter with a sand core funnel, combine the organic phases, and remove the solvent by rotary evaporation. Finally, the crude product can be separated by silica gel column chromatography to obtain a colorless oily liquid target product with a separation yield of 88%, and the deuteration rate is >99%. 1 H NMR (400 MHz, CDCl 3 )δ7.99(1H, s), 7.84–7.78(3H, m), 7.54–7.48(3H, m); 13 C NMR (101 MHz, CDCl 3 )δ132.9, 132.7, 131.3, 128.4, 128.0, 127.8, 127.7, 126.6, 126.6, 120.8, 98.7, 71.9, 9.8–9.0 (m, CD 3 ); HRMS(APCI + )[M+Na] + Calculated value C 13 H 7 D 3 NaSe: 266.0088, measured value: 266.0084.

[0082] Application Example 10.

[0083]

[0084] Specific operation steps: place a 25.0 mL sealed tube in an oven at 120°C for 1-2 hours, put in a magnetic bar, cool to room temperature, ventilate 3 times under a nitrogen atmosphere, add 0.5 mmol of 4-methoxyphenylacetylene, 0.75 mmol of deuterated reagent, 0.025 mmol of cuprous iodide, 0.03 mmol of 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene and 0.75 mmol of potassium carbonate, ventilate 3 times under a nitrogen atmosphere, add 5.0 mL of ultra-dry dimethyl sulfoxide, stir and react at 22°C for 24 hours, pour the reaction solution into 25.0 mL of water, extract the organic phase with dichloromethane (30.0 mL×3), combine the organic phases and back-extract with water 3 times, then dry with anhydrous sodium sulfate for 15 minutes, filter with a sand core funnel, combine the organic phases, and remove the solvent by rotary evaporation. Finally, the crude product can be separated by silica gel column chromatography to obtain the yellow oily liquid target product with a separation yield of 81%, and the deuteration rate is >99%. 1 H NMR (400 MHz, CDCl 3 )

[0085] δ7.38 (2H, d, J=8.8Hz), 6.82 (2H, d, J=8.9Hz), 3.79 (3H, s); 13 C NMR (101 MHz, CDCl 3 )

[0086] δ159.6, 133.3, 115.6, 113.9, 98.0, 69.2, 55.3, 9.8–8.9 (m, CD 3 ); HRMS(APCI + )[M+H] + Calculated value C 10 H 8 D 3 OSe: 224.0217, measured value: 224.0217.

[0087] Application Example 11.

[0088]

[0089] Specific operation steps: place a 25.0mL sealed tube in a 120℃ oven for 1-2 hours, put in a magnetic bar, cool to room temperature, ventilate 3 times under a nitrogen atmosphere, add 0.5mmol deuterated reagent, 0.75mmol 4-methoxyphenylboronic acid, 0.025mmol copper sulfate and 1.0mmol sodium bicarbonate, ventilate 3 times under a nitrogen atmosphere, add 5.0mL ultra-dry methanol, stir and react at 30℃ for 12h, pour the reaction solution into 30.0mL water, extract the organic phase with dichloromethane (30.0mL×3), combine the organic phases and back-extract with water 3 times, then dry with anhydrous sodium sulfate for 15min, filter with a sand core funnel, combine the organic phases, and remove the solvent by rotary evaporation. Finally, the crude product can be separated by silica gel column chromatography to obtain a colorless oily liquid target product with a separation yield of 90%, and the deuteration rate is>99%. 1 H NMR (400 MHz, CDCl 3 ) δ7.42 (2H, d, J = 8.9Hz), 6.83 (2H, d, J = 8.9Hz), 3.79 (3H, s); 13 C NMR (101 MHz, CDCl 3 )δ158.8, 133.4, 121.4, 114.8, 55.2, 8.5–7.6 (m, CD 3 ); HRMS(ESI + )[M+Na] + Calculated value C 8 H 7 D 3 NaOSe: 222.0037, measured value: 222.0040. H NMR spectrum Figure 1 , NMR carbon spectrum such as Figure 2 .

[0090] Application Example 12.

[0091]

[0092] Specific operation steps: Place 25.0mL sealed tube in a 120℃ oven for 1-2 hours, put in a magnetic bar, cool to room temperature, ventilate 3 times under nitrogen atmosphere, add 0.5mmol deuterated reagent, 0.75mmol 4-chlorophenylboronic acid, 0.025mmol copper sulfate and 1.0mmol sodium bicarbonate, ventilate 3 times under nitrogen atmosphere, add 5.0mL ultra-dry methanol, stir and react at 30℃ for 12h, pour the reaction solution into 30.0mL water, extract the organic phase with dichloromethane (30.0mL×3), combine the organic phases and back-extract with water 3 times, then dry with anhydrous sodium sulfate for 15min, filter with a sand core funnel, combine the organic phases, and remove the solvent by rotary evaporation. Finally, the crude product can be separated by silica gel column chromatography to obtain a colorless oily liquid target product with a separation yield of 87%, and the deuteration rate is>99%. 1 HNMR (500 MHz, CDCl 3 ) δ7.34 (2H, d, J = 8.5Hz), 7.22 (2H, d, J = 8.5Hz); 13 C NMR (101 MHz, CDCl 3 )δ132.2, 131.7, 130.1, 129.2, 7.5–6.6 (m, CD 3 ); HRMS(ESI + )[M+Na] + Calculated value C 7 H 4 D 3 ClNaSe: 225.9542, measured value: 225.9545.

[0093] Application Example 13.

[0094]

[0095] Specific operation steps: Place the 25.0mL sealed tube in a 120℃ oven for 1-2 hours, put in a magnetic bar, cool to room temperature, ventilate 3 times under nitrogen atmosphere, add 0.5mmol deuterated reagent, 0.75mmol 4-methyl formate phenylboronic acid, 0.025mmol copper sulfate and 1.0mmol sodium bicarbonate, ventilate 3 times under nitrogen atmosphere, add 5.0mL ultra-dry methanol, stir and react at 30℃ for 12h, pour the reaction solution into 30.0mL water, extract the organic phase with dichloromethane (30.0mL×3), combine the organic phases and back-extract with water 3 times, then dry with anhydrous sodium sulfate for 15min, filter with a sand core funnel, combine the organic phases, and remove the solvent by rotary evaporation. Finally, the crude product can be separated by silica gel column chromatography to obtain the white solid target product with a separation yield of 96%, and the deuteration rate is >99%. Melting point = 77.7–78.2℃. 1 H NMR (400 MHz, CDCl3 ) δ7.88 (2H, d, J = 8.4Hz), 7.38 (2H, d, J = 8.5Hz), 3.88 (3H, s); 13 C NMR (101 MHz, CDCl 3 )δ166.9, 139.6, 129.9, 128.6, 127.4, 52.1, 6.4–5.5 (m, CD 3 ); HRMS(ESI + )[M+Na] + Calculated value C 9 H 7 D 3 NaO 2 Se: 249.9986, measured value: 249.9986.

[0096] Application Example 14.

[0097]

[0098] Specific operation steps: Place the 25.0mL sealed tube in a 120℃ oven for 1-2 hours, put in a magnetic bar, cool to room temperature, ventilate 3 times under nitrogen atmosphere, add 0.5mmol deuterated reagent, 0.75mmol 4-acetylphenylboronic acid, 0.025mmol copper sulfate and 1.0mmol sodium bicarbonate, ventilate 3 times under nitrogen atmosphere, add 5.0mL ultra-dry methanol, stir and react at 30℃ for 12h, pour the reaction solution into 30.0mL water, extract the organic phase with dichloromethane (30.0mL×3), combine the organic phases and back-extract with water 3 times, then dry with anhydrous sodium sulfate for 15min, filter with a sand core funnel, combine the organic phases, and remove the solvent by rotary evaporation. Finally, the crude product can be separated by silica gel column chromatography to obtain the white solid target product with a separation yield of 97%, and the deuteration rate is >99%. Melting point = 68.4–68.9℃. 1 H NMR (400 MHz, CDCl 3 ) δ7.80 (2H, d, J = 8.5Hz), 7.39 (2H, d, J = 8.5Hz), 2.54 (3H, s); 13 C NMR (101 MHz, CDCl 3 )δ197.4, 140.2, 134.5, 128.7, 128.6, 26.5, 6.3–5.5 (m, CD 3 ); HRMS(APCI + )[M+H] + Calculated value C 9 H 8 D 3 OSe: 212.0217, measured value: 212.0215.

[0099] Application Example 15.

[0100]

[0101] Specific operation steps: Place the 25.0mL sealed tube in a 120℃ oven for 1-2 hours, put in a magnetic bar, cool to room temperature, ventilate 3 times under nitrogen atmosphere, add 0.5mmol deuterated reagent, 0.75mmol 4-methyl sulfide phenylboronic acid, 0.025mmol copper sulfate and 1.0mmol sodium bicarbonate, ventilate 3 times under nitrogen atmosphere, add 5.0mL ultra-dry methanol, stir and react at 30℃ for 12h, pour the reaction solution into 30.0mL water, extract the organic phase with dichloromethane (30.0mL×3), combine the organic phases and back-extract with water 3 times, then dry with anhydrous sodium sulfate for 15min, filter with a sand core funnel, combine the organic phases, and remove the solvent by rotary evaporation. Finally, the crude product can be separated by silica gel column chromatography to obtain the white solid target product with a separation yield of 95%, and the deuteration rate is >99%. Melting point = 72.7–73.1℃. 1 H NMR (400 MHz, CDCl 3 ) δ7.35 (2H, d, J = 8.4Hz), 7.16 (2H, d, J = 8.4Hz), 2.46 (3H, s); 13 C NMR (101 MHz, CDCl 3 )δ136.5, 131.3, 128.0, 127.4, 16.1, 7.5–6.7 (m, CD 3 ); HRMS(APCI + )[M+Na] + Calculated value C 8 H 7 D 3 NaSSe: 237.9808, measured value: 237.9812.

[0102] Application Example 16.

[0103]

[0104] Specific operation steps: Place 25.0mL sealed tube in a 120℃ oven for 1-2 hours, put in a magnetic bar, cool to room temperature, ventilate 3 times under nitrogen atmosphere, add 0.5mmol deuterated reagent, 0.75mmol 4-methoxyphenylboronic acid pinacol ester, 0.05mmol copper sulfate and 1.0mmol sodium bicarbonate, ventilate 3 times under nitrogen atmosphere, add 5.0mL ultra-dry methanol, stir and react at 30℃ for 24h, pour the reaction solution into 30.0mL water, extract the organic phase with dichloromethane (30.0mL×3), combine the organic phases and back-extract with water 3 times, then dry with anhydrous sodium sulfate for 15min, filter with a sand core funnel, combine the organic phases, and remove the solvent by rotary evaporation. Finally, the crude product can be separated by silica gel column chromatography to obtain a colorless oily liquid target product with a separation yield of 60%, and the deuteration rate is>99%. The target product is the same as Example 11, 1 H NMR (400 MHz, CDCl 3 ) δ7.42 (2H, d, J = 8.9Hz), 6.83 (2H, d, J = 8.9Hz), 3.79 (3H, s); 13 C NMR (101 MHz, CDCl 3 )δ158.8, 133.4, 121.4, 114.8, 55.2, 8.5–7.6 (m, CD 3 ); HRMS(ESI + )[M+Na] + Calculated value C 8 H 7 D 3 NaOSe: 222.0037, measured value: 222.0040.

[0105] Application Example 17.

[0106]

[0107] Specific operation steps: Place the 25.0mL sealed tube in a 120℃ oven for 1-2 hours, put in a magnetic bar, cool to room temperature, ventilate 3 times under nitrogen atmosphere, add 0.5mmol deuterated reagent, 0.75mmol 4-iodophenylboronic acid pinacol ester, 0.05mmol copper sulfate and 1.0mmol sodium bicarbonate, ventilate 3 times under nitrogen atmosphere, add 5.0mL ultra-dry methanol, stir and react at 30℃ for 24h, pour the reaction solution into 30.0mL water, extract the organic phase with dichloromethane (30.0mL×3), combine the organic phases and back-extract with water 3 times, then dry with anhydrous sodium sulfate for 15min, filter with a sand core funnel, combine the organic phases, and remove the solvent by rotary evaporation. Finally, the crude product can be separated by silica gel column chromatography to obtain the target product as a white solid with a separation yield of 95%, and the deuteration rate is >99%. Melting point = 50.5–51.2℃.1 H NMR (400 MHz, CDCl 3 ) δ7.55 (2H, d, J = 8.4Hz), 7.13 (2H, d, J = 8.4Hz); 13 C NMR (101 MHz, CDCl 3 )δ137.9, 132.0, 91.1, 7.2–6.4 (m, CD 3 ); HRMS(ESI + )[M+Na] + Calculated value C 7 H 4 D 3 INaSe: 317.8898, measured value: 317.8901.

[0108] Application Example 18.

[0109]

[0110] Specific operation steps: Place the 25.0mL sealed tube in a 120℃ oven for 1-2 hours, put in a magnetic bar, cool to room temperature, ventilate 3 times under a nitrogen atmosphere, add 0.5mmol deuterated reagent, 0.75mmol 4-methyl formate phenylboronic acid pinacol ester, 0.05mmol copper sulfate and 1.0mmol sodium bicarbonate, ventilate 3 times under a nitrogen atmosphere, add 5.0mL ultra-dry methanol, stir and react at 30℃ for 24h, pour the reaction solution into 30.0mL water, extract the organic phase with dichloromethane (30.0mL×3), combine the organic phases and back-extract with water 3 times, then dry with anhydrous sodium sulfate for 15min, filter with a sand core funnel, combine the organic phases, and remove the solvent by rotary evaporation. Finally, the crude product can be separated by silica gel column chromatography to obtain a white solid target product with a separation yield of 96%, and the deuteration rate is>99%. The target product is the same as Example 13, with a melting point of 77.7–78.2℃. 1 H NMR (400 MHz, CDCl 3 ) δ7.88 (2H, d, J = 8.4Hz), 7.38 (2H, d, J = 8.5Hz), 3.88 (3H, s); 13 C NMR (101 MHz, CDCl 3 )δ166.9, 139.6, 129.9, 128.6, 127.4, 52.1, 6.4–5.5 (m, CD 3 ); HRMS(ESI + )[M+Na] + Calculated value C 9 H 7 D 3 NaO 2Se: 249.9986, measured value: 249.9986.

[0111] Application Example 19.

[0112]

[0113] Specific operation steps: Place the 25.0mL sealed tube in a 120℃ oven for 1-2 hours, put in a magnetic bar, cool to room temperature, ventilate 3 times under nitrogen atmosphere, add 0.5mmol deuterated reagent, 0.75mmol 4-diphenylboronic acid pinacol ester, 0.05mmol copper sulfate and 1.0mmol sodium bicarbonate, ventilate 3 times under nitrogen atmosphere, add 5.0mL ultra-dry methanol, stir and react at 30℃ for 24h, pour the reaction solution into 30.0mL water, extract the organic phase with dichloromethane (30.0mL×3), combine the organic phases and back-extract with water 3 times, then dry with anhydrous sodium sulfate for 15min, filter with a sand core funnel, combine the organic phases, and remove the solvent by rotary evaporation. Finally, the crude product can be separated by silica gel column chromatography to obtain the white solid target product with a separation yield of 79%, and the deuteration rate is >99%. Melting point = 101.7–102.4℃. 1 H NMR (400 MHz, CDCl 3 ) δ7.63 (2H, d, J = 7.8Hz), 7.54 (4H, s), 7.49 (2H, dd, J = 7.2, 7.5Hz), 7.40 (1H, dd, J = 7.5, 7.0Hz); 13 C NMR (101 MHz, CDCl 3 )δ140.6, 139.1, 131.0, 130.7, 128.9, 127.7, 127.4, 126.9, 7.2–6.3 (m, CD 3 ); HRMS(ESI + )[M+Na] + Calculated value C 13 H 9 D 3 NaSe: 268.0244, measured value: 268.0249.

[0114] Application Example 20.

[0115]

[0116] Specific operation steps: Place 25.0mL sealed tube in a 120℃ oven for 1-2 hours, put in a magnetic bar, cool to room temperature, ventilate 3 times under nitrogen atmosphere, add 0.5mmol deuterated reagent, 0.75mmol 1-THP-4-pyrazole boronic acid pinacol ester, 0.05mmol copper sulfate and 1.0mmol sodium bicarbonate, ventilate 3 times under nitrogen atmosphere, add 5.0mL ultra-dry methanol, stir and react at 30℃ for 24h, pour the reaction solution into 30.0mL water, extract the organic phase with dichloromethane (30.0mL×3), combine the organic phases and back-extract with water 3 times, then dry with anhydrous sodium sulfate for 15min, filter with a sand core funnel, combine the organic phases, and remove the solvent by rotary evaporation. Finally, the crude product can be separated by silica gel column chromatography to obtain a colorless oily liquid target product with a separation yield of 98%, and the deuteration rate is>99%. 1 H NMR (400 MHz, CDCl 3 )δ7.61 (1H, s), 7.51 (1H, s), 5.31 (1H, d, J = 11.8Hz), 4.00 (1H, d, J = 12.4Hz), 3.64 (1H, t, J = 10.6Hz,), 2.09–1.98 (3H, m), 1.65–1.55 (3H, m); 13 C NMR (101 MHz, CDCl 3 )δ143.7, 131.5, 103.5, 87.5, 67.7, 30.3, 24.8, 22.3, 9.9–9.1 (m, CD 3 ); HRMS(ESI + )[M+Na] + Calculated value C 9 H 11 D 3 N 2 NaOSe: 266.0411, measured value: 266.0421.

Claims

1. A method for synthesizing an electrophilic selenide deuterated methyl reagent, characterized in that: Step (1) placing the container in an oven for drying, placing a magnet in the container after drying, ventilating the container under a nitrogen atmosphere to ensure that the container is in a nitrogen environment, and cooling the container to room temperature; Step (2) adding sodium p-toluenesulfinate and selenium powder in a molar ratio of 1:1 into the container, ventilating under a nitrogen atmosphere to ensure that the container is a nitrogen environment, and then sealing the container; Step (3) adding D3-toluenesulfonyl methyl ester and an organic solvent in a sealed state, wherein the molar ratio of D3-toluenesulfonyl methyl ester to sodium p-toluenesulfinate is (0.75-0.95):1, and 1.5-2.5 ml of the organic solvent is added per mmol of sodium toluenesulfinate; Step (4) is stirred and reacted at room temperature for 18 to 30 hours, and the reaction formula is as follows: After the reaction in step (5) is completed, the reaction solution is poured into water, the organic phase is extracted with ethyl acetate 2 to 3 times, and the organic phases are combined; back-extracted with water 3 to 6 times, and then dried with anhydrous sodium sulfate, filtered and evaporated to remove the solvent; the crude product is chromatographed on a silica gel column to obtain selenium-(methyl-d3) p-methylphenylsulfonic acid selenoester.

2. The method for synthesizing an electrophilic selenide deuterated methyl reagent as claimed in claim 1, wherein: The organic solvent is N,N-dimethylformamide solvent or N,N-dimethylacetamide solvent.

3. Application of the electrophilic deuterated selenium methyl reagent prepared by the method as claimed in claim 1 or 2 as the preparation of trideuterated methyl selenoether.

4. The use of the electrophilic deuterated selenium methyl reagent as claimed in claim 3 for preparing trideuterated methyl selenoether, characterized in that: The trideuterated methylselenoether is trideuterated methylselenoalkyl ether, and the applied substrate is β-ketoester.

5. The use of the electrophilic deuterated selenium methyl reagent as claimed in claim 4 for preparing trideuterated methyl selenoether, characterized in that: The β-ketoester is 1-oxo-2,3-dihydro-1H-indene-2-carboxylic acid methyl ester or 5-chloro-1-oxo-2,3-dihydro-1H-indene-2-carboxylic acid methyl ester or 5-bromo-1-oxo-2,3-dihydro-1H-indene-2-carboxylic acid methyl ester or 1-oxo-2,3-dihydro-1H-indene-2-carboxylic acid ethyl ester or 1-oxo-2,3-dihydro-1H-indene-2-carboxylic acid 1,1-dimethylethyl ester 6. The use of the electrophilic deuterated selenium methyl reagent as claimed in claim 3 for preparing trideuterated methyl selenide, characterized in that: The trideuterated methylselenoether is trideuterated methylselenoynyl ether, and the applied substrate is a terminal alkyne derivative.

7. The use of the electrophilic deuterated selenium methyl reagent as claimed in claim 6 for preparing trideuterated methyl selenoether, characterized in that: The terminal alkyne derivative is phenylacetylene or 4-bromophenylacetylene or methyl 4-ethynylbenzoate or 2-naphthylacetylene or 4-methoxyphenylacetylene 8. The use of the electrophilic deuterated selenium methyl reagent as claimed in claim 3 for preparing trideuterated methyl selenide, characterized in that: The trideuterated methyl selenide is trideuterated methyl selenide aryl ether, and the applied substrate is aryl boronic acid or aryl boronic acid pinacol ester.

9. The use of the electrophilic deuterated selenium methyl reagent as claimed in claim 8 for preparing trideuterated methyl selenoether, characterized in that: The aryl boronic acid is 4-methoxyphenylboronic acid or 4-chlorophenylboronic acid or 4-methyl formate phenylboronic acid or 4-acetylphenylboronic acid or 4-methyl sulfide phenylboronic acid 10. Use of the electrophilic deuterated selenium methyl reagent as claimed in claim 8 for preparing trideuterated methyl selenoether, characterized in that: The aryl boronic acid pinacol ester is 4-methoxyphenyl boronic acid pinacol ester. or 4-iodophenylboronic acid pinacol ester or 4-Methyl phenylboronic acid pinacol ester or 4-Bis(phenylboronic acid)pinacol ester or 1-THP-4-pyrazoleboronic acid pinacol ester

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