Synthesis technology for preparing alpha-deuterated amine compound

Abstract

The invention relates to a synthesis method for preparing an alpha-deuterated amine compound in the technical field of medicines, and belongs to the technical field of chemical pharmacy. The invention particularly relates to a synthesis method of an alpha-deuterated amine compound shown as a formula I. The general formula of the alpha-deuterated amine compound is as shown in a formula I in the specification. The alpha-deuterated amine compound is generated by taking corresponding amine as a substrate, thiol as a catalyst, heavy water as a deuterium source, aromatic acid ester as an additive and esters as a reaction solvent under light irradiation. The compound can be used for drug development or synthesis of other types of deuterated molecules. # imgabs0 #

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for preparing alpha-deuterated amine by deuteration through H / D exchange. Technical Background

[0002] Deuterium is an isotope of hydrogen. Deuterated compounds have important and widespread applications in many fields. Deuterated compounds are used in drug development to improve the stability and bioavailability of drugs. Deuterated drugs (such as deuterated fluoxetine) have shown better pharmacokinetic properties in clinical trials. Deuterated compounds can also be used as tracers to help study metabolic pathways and biotransformation processes. By tracking deuterium-labeled compounds, scientists can better understand chemical reactions in organisms. Deuterated compounds can reduce the signal interference of hydrogen in nuclear magnetic resonance analysis, thereby improving the ability to analyze the structure of compounds. Deuterated compounds provide important clues in reaction mechanism research, helping scientists understand the details of chemical reactions. Therefore, it is of great significance to develop efficient preparation methods for deuterated compounds.

[0003] At present, the methods for deuteration of compounds can be roughly divided into three categories: reductive deuteration, dehalogenation, and hydrogen-deuterium exchange (HDE). HDE has the highest efficiency because it does not require the introduction and conversion of functional groups. With the rapid development of photochemistry in recent years, free radical-mediated HDE has gained wide attention. The key steps usually include the generation and deuteration of carbon radicals. Carbon radicals can be generated by proton-coupled electron transfer (PCET) or photocatalyst-catalyzed hydrogen atom transfer (HAT). The thiol-d1 generated in situ by the reaction of HDE with heavy water usually serves as a deuterium atom donor to complete the deuteration step.

[0004] Amines are not only widely present in natural products, but also play a vital role in chemical and drug synthesis. Amines are widely present in drug molecules and can be used to synthesize other compounds. Since the N atom has a lone pair of electrons, it is easily oxidized, causing the carbon at the N-adjacent position to be easily metabolized in the body, thereby reducing the stability of the drug. However, when the hydrogen on the N-adjacent carbon is replaced by deuterium, its metabolic rate decreases significantly, thereby increasing the half-life of the compound. Photocatalytic hydrogen-deuterium exchange (HDE) of N-adjacent CH is an ideal method due to its high synthesis efficiency. However, the current photocatalytic HDE method requires the use of a photocatalyst. The use of a photocatalyst will increase the cost of the synthesis and separation and removal of the catalyst, and is not conducive to industrial promotion. Summary of the invention

[0005] The object of the present invention is to provide a method for preparing α-deuterated amine. The method uses amine as a substrate, heavy water as a deuterium source, thiol and aromatic acid ester as additives, and esters as solvents to prepare α-deuterated amine by HDE under 380nm light. The method has the advantages of high operability, good deuteration effect, and no catalyst.

[0006] The technical solution adopted by the present invention to solve its technical problem is:

[0007] A method for preparing α-deuterated amine by HDE, which takes amine as substrate, reacts under light in a reaction system consisting of thiol, aromatic ester, deuterium source reagent and solvent; after the reaction is completed, the product is separated and purified to obtain a compound shown in formula I.

[0008] Where R 1 is aryl, substituted aryl, polycyclic aryl, heterocyclic aryl, substituted heterocyclic aryl, polycyclic aryl, C 1-18 Alkyl, C 1-10 Cycloalkyl. The N atom may also be in a saturated aliphatic ring. Including but not limited to the following compounds:

[0009]

[0010] The preferred molar ratio of substrate, thiol, aromatic acid ester and heavy water is 1:0.05-0.3:0.5-1:40-100.

[0011] Preferably, the mercaptan is selected from one or two of triisopropylsilylmercaptan, triphenylsilylmercaptan and phenylethylmercaptan. Triisopropylsilylmercaptan has been fully H / D exchanged with heavy water before being added into the reaction.

[0012] The aromatic acid ester is selected from methyl benzoate and methyl nicotinate.

[0013] Preferably, the deuterium source reagent is selected from heavy water.

[0014] The anhydrous solvent is selected from anhydrous acetonitrile, anhydrous acetone, anhydrous 1,2-dichloroethane, anhydrous dichloromethane, anhydrous chloroform, anhydrous ethyl acetate, anhydrous methyl propionate, anhydrous ethyl propionate, anhydrous methyl formate, anhydrous ethyl formate or a mixed solvent of any two thereof. Preferably, esters are used as solvents.

[0015] The wavelength of the light used may be any wavelength or wavelength band between 365 nm and 450 nm, but is preferably any wavelength or wavelength band between 380 nm and 400 nm.

[0016] The reaction time is greater than or equal to 24 hours.

[0017] The beneficial effects of the present invention are: 1) no additional photocatalyst is required in the photoreaction, and it can be effectively completed using a cheap deuterium source, the reaction is highly operable, and the deuteration effect is good; 2) the process method has good universality and can be used for the preparation of a variety of α-deuterated amine products; 3) it is safe, green, and cheap. DETAILED DESCRIPTION

[0018] The technical solution of the present invention is further described in detail below through specific embodiments.

[0019] In the present invention, unless otherwise specified, the raw materials and equipment used can be purchased from the market or are commonly used in the art. The methods in the following embodiments, unless otherwise specified, are all conventional methods in the art.

[0020] Example 1, Preparation of Compound 1

[0021] At room temperature, under an argon atmosphere, N-methyldiphenylamine (36 mg, 0.2 mmol, 1.0 equiv), triisopropylsilanethiol (60 uL, 30 mol%), heavy water (160 uL, 40 equiv) methyl benzoate (13 uL, 0.5 equiv) and 1.0 mL of anhydrous ethyl acetate were added to the reaction tube. The solution was degassed by freeze-pump-thaw and then plugged with a rubber stopper. The reaction solution was stirred for a certain period of time at 40 ° C and a 380 nm LED. After the reaction was completed, the reaction solution was concentrated. After the reaction was completed, the reaction solution was concentrated and the target compound 1 was separated by column chromatography as a yellow oil. (38 mg, 79% yield, 94% D ratio by 1 H NMR). 1 HNMR (400MHz, CDCl3) δ9.97 (s, 0.05H), 7.78 (d, J = 7.6Hz, 2H), 7.34 (d, J = 7.7Hz, 2H), 2.44 (s, 3H). 13 C NMR (100MHz, CDCl3) δ191.99–191.41(m),145.56,134.16,129.85,129.72.

[0022] H / D exchange method of compound triisopropylsilanethiol with heavy water

[0023] Triisopropylsilanethiol (1.0 mmol) was dissolved in 1.0 mL of anhydrous ethyl acetate, and then deuterated water (10 mmol) was added. After stirring for 1 hour, the solution was allowed to stand and separate into layers, and the supernatant was used for the reaction.

[0024] The preparation methods of the remaining compounds are the same as 1. Various α-deuterated amine compounds can be obtained after the above reaction conditions. The results are shown in Table 1:

[0025] Table 1

[0026] Example 2, Preparation of Compound 2

[0027] The method is the same as Example 1, except that the amount of substrate is 0.4 mmol, methyl nicotinate (27 mg, 0.5 equivalent) is used instead of methyl benzoate, and the reaction time is 24 hours. 39 mg of yellow oil is obtained, and the yield is 77%. 1 H NMR (400MHz, CDCl3) δ7.35–7.06 (m, 2H), 6.71 (dt, J = 10.7, 5.2Hz, 3H), 2.88 (s, 0. 42H).13CNMR(100MHz, CDCl3)δ150.81,129.11,116.67,112.69,40.20–39.51(m).

[0028] Example 3, Preparation of Compound 3

[0029] The method is the same as Example 1, except that the amount of substrate is 0.4 mmol, methyl nicotinate (27 mg, 0.5 equivalent) is used instead of methyl benzoate, and the reaction time is 36 hours. 45.5 mg of yellow oil is obtained, with a yield of 81%. 1 H NMR (400MHz, CDCl3) δ7.05 (d, J = 6.8 Hz, 2H), 6.68 (d, J = 6.8 Hz, 2H), 2.84 (dt, J = 4.2, 1.9 Hz, 0.51H, 92% D), 2.25 (t, J = 4.9 Hz, 2.52H, 16% D). 13 C NMR (100MHz, CDCl3) δ148.96, 129.66, 126.09, 113.23, 41.34–39.56 (m), 20.35–19.83 (m).

[0030] Example 4, Preparation of Compound 4

[0031] The method is the same as Example 1, except that the amount of substrate is 0.4 mmol, methyl nicotinate (55 mg, 1 equivalent) is used instead of methyl benzoate, and the reaction time is 48 hours. 83 mg of yellow oil is obtained, with a yield of 98%. 1 H NMR (400MHz, CDCl3) δ6.83 (d, J = 9.1Hz, 2H), 6.73 (d, J = 9.2Hz, 2H), 2.89–2.74 (m, 0.41H). 13CNMR (100MHz, CDCl3) δ 152.03, 145.87, 114.87, 114.85, 114.71, 55.79, 41.03 (dt, J = 28.2, 20.3Hz).

[0032] Example 5, Preparation of Compound 5

[0033] The method is the same as Example 1, except that the amount of substrate is 0.4 mmol, methyl nicotinate (27 mg, 0.5 equivalent) is used instead of methyl benzoate, and the reaction time is 36 hours. 57 mg of yellow oil is obtained, with a yield of 90%. 1 H NMR (400MHz, CDCl3) δ7.13(t,J=8.1Hz,1H),6.34(d,J=8.4Hz,1H),6.27(d,J=12.5Hz,2H),3.77(s,3H),2.87(dq,J=4.3,2.1Hz,0.45H). 13 C NMR (100MHz, CDCl3) δ160.77,152.12,129.80,105.75,101.43,99.13,55.13,40.51–39.24(m).

[0034] Example 6, Preparation of Compound 6

[0035] The method is the same as Example 1, except that the amount of substrate is 0.4 mmol, methyl nicotinate (27 mg, 0.5 equivalent) is used instead of methyl benzoate, and the reaction time is 36 hours. 58 mg of white solid is obtained, with a yield of 93%. 1 H NMR (400MHz, CDCl3) δ7.90 (d, J = 9.1Hz, 2H), 6.62 (d, J = 9.1Hz, 2H), 3.85 (s, 3H), 3.00–2.90 (m, 0.43H). 13 C NMR (100MHz, CDCl3) δ167.52,153.35,131.27,116.87,110.63,51.48,39.87–38.65(m).

[0036] Example 7, Preparation of Compound 7

[0037] The method is the same as Example 1, except that the amount of substrate is 0.4 mmol, methyl nicotinate (27 mg, 0.5 equivalent) is used instead of methyl benzoate, and the reaction time is 36 hours. 61 mg of white solid is obtained, with a yield of 82%. 1H NMR (400MHz, CDCl3) δ7.43–7.33(m,2H),7.31–7.23(m,1H),6.88(d,J=9.5Hz,1H),3.89(s,3H),2.93(p,J=1.9Hz,0.6H). 13 C NMR (100MHz, CDCl3) δ167.81,150.52,130.80,129.00,117.50,116.68,113.15,51.99,40.42–39.32(m).

[0038] Example 8, Preparation of Compound 8

[0039] The method is the same as Example 1, except that the amount of substrate is 0.4 mmol, methyl nicotinate (27 mg, 0.5 equivalent) is used instead of methyl benzoate, and the reaction time is 24 hours. 61 mg of yellow solid is obtained, with a yield of 88%. 1 H NMR (400MHz, CDCl3) δ7.85 (d, J = 9.1Hz, 2H), 6.62 (d, J = 9.0Hz, 2H), 3.00 (dq, J = 3.7, 2.1Hz, 0.44H, 93%D), 2.53-2.45 (m, 2.32H, 23%D). 13 C NMR (100MHz, CDCl3) δ196.40,153.46,130.53,125.23,110.52,39.89–38.61(m),26.06–25.41(m).

[0040] Example 9, Preparation of Compound 9

[0041] The method is the same as Example 1, except that the amount of substrate is 0.4 mmol and the reaction time is 36 hours. 34 mg of yellow oil is obtained with a yield of 50%. 1 H NMR (400MHz, CDCl3) δ7.36–7.23 (m, 3H), 6.91 (d, J = 8.1Hz, 1H), 3.00–2.93 (m, 0.51H, 92%D), 2.62–2.54 (m, 2.04H, 32%D). 13 C NMR (100MHz, CDCl3) δ199.04,150.69,137.92,129.16,117.02,116.88,111.16,40.17–39.35(m),26.79–26.11(m).

[0042] Example 10, Preparation of Compound 10

[0043] The method is the same as Example 1, except that the amount of substrate is 0.4 mmol, methyl nicotinate (27 mg, 0.5 equivalent) is used instead of methyl benzoate, and the reaction time is 24 hours. 52 mg of yellow oil is obtained, with a yield of 81%. 1 H NMR (400MHz, CDCl3) δ7.15 (d, J = 9.0Hz, 2H), 6.60 (d, J = 9.1Hz, 2H), 2.85 (p, J = 1.9Hz, 0.4H). 13 C NMR (100MHz, CDCl3) δ149.27, 128.84, 121.35, 113.60, 39.90 (dt, J = 27.5, 20.6Hz).

[0044] Example 11, Preparation of Compound 11

[0045] The method is the same as Example 1, except that the amount of substrate is 0.4 mmol, methyl nicotinate (27 mg, 0.5 equivalent) is used instead of methyl benzoate, and the reaction time is 24 hours. 69 mg of yellow oil is obtained with a yield of 84%. 1 H NMR (400MHz, CDCl3) δ7.28 (dd, J=9.0, 3.5Hz, 2H), 6.56 (dd, J=9.0, 3.5Hz, 2H), 2.96–2.78 (m, 0.4H). 13 C NMR (100MHz, CDCl3) δ149.62,131.70,114.08,108.49,40.10–39.41(m).

[0046] Example 12, Preparation of Compound 12

[0047] The method is the same as Example 1, except that the amount of substrate is 0.4 mmol, methyl nicotinate (27 mg, 0.5 equivalent) is used instead of methyl benzoate, and the reaction time is 36 hours. 68 mg of yellow oil is obtained, with a yield of 83%. 1 H NMR (400MHz, CDCl3) δ7.05(td,1H),6.81(d,2H),6.59(d,1H),2.87(dt,0.43H). 13 C NMR (100MHz, CDCl3) δ151.77,130.26,123.42,119.09,115.10,110.91,40.25–38.94(m).

[0048] Example 13, Preparation of Compound 13

[0049] The method is the same as Example 1, except that the amount of substrate is 0.4 mmol, methyl nicotinate (27 mg, 0.5 equivalent) is used instead of methyl benzoate, and the reaction time is 36 hours. 63 mg of yellow oil is obtained, with a yield of 89%. 1 H NMR (400MHz, CDCl3) δ8.22(d,J=10.4Hz,1H),7.78(d,J=7.9Hz,1H),7.51–7.37(m ,3H),7.35(t,J=7.9Hz,1H),7.02(d,J=7.6Hz,1H),2.81(h,J=2.3,1.7Hz,0.46H). 13 C NMR (100MHz, CDCl3) δ150.97,134.96,128.93,128.45,125.88,125.79,125.21,124.27,122.93,113.94,113.92,45.20–43.67(m).

[0050] Example 14, Preparation of Compound 14

[0051] The method is the same as Example 1, except that the amount of substrate is 0.4 mmol and the reaction time is 36 hours. 57 mg of yellow oil is obtained with a yield of 99%. 1 H NMR (400MHz, CDCl3) δ7.06(t,J=8.0Hz,1H),6.34(s,1H),6.21(d,J=7.3Hz,2H),5.65(s,1H),2.88–2.71(m,0.45H). 13 C NMR (100MHz, CDCl3) δ156.72,152.28,130.08,105.92,104.60,100.61,40.77–39.51(m).

[0052] Example 15, Preparation of Compound 15

[0053] The method is the same as Example 1, except that the amount of substrate is 0.4 mmol, methyl nicotinate (27 mg, 0.5 equivalent) is used instead of methyl benzoate, and the reaction time is 36 hours. 41 mg of brown solid is obtained, with a yield of 56%. 1 H NMR (400MHz, CDCl3) δ9.70 (s, 0.09H, 91%D), 7.72 (d, J = 8.7Hz, 2H), 6.55 (d, J = 9.0Hz, 2H), 3.41-3.32 (m, 0.21H, 95%D), 2.03 (s, 4H). 13CNMR(100MHz, CDCl3)δ190.23–189.60(m),152.10,124.69,111.18,47.57–46.54(m),25.20.

[0054] Example 16, Preparation of Compound 16

[0055] The method is the same as Example 1, except that the amount of substrate is 0.4 mmol, methyl nicotinate (27 mg, 0.5 equivalent) is used instead of methyl benzoate, heavy water is (640 μL, 80 equiv), and the reaction time is 36 hours. 50 mg of yellow oil is obtained with a yield of 81%. 1 H NMR (400MHz, CDCl3) δ9.73 (s, 0.04H, 96%D), 7.72 (d, J = 8.9Hz, 2H), 6.68 (d, J = 9.0Hz, 2H), 3.03 (p, J = 2.1Hz, 0.56H, 91%D). 13 C NMR (100MHz, CDCl3) δ190.24–189.63(m),154.44,131.95,125.13–124.98(m),110.95,39.87–38.71(m).

[0056] Example 17, Preparation of Compound 17

[0057] The method is the same as Example 1, except that the amount of substrate is 0.4 mmol, methyl nicotinate (27 mg, 0.5 equivalent) is used instead of methyl benzoate, and the reaction time is 36 hours. 47 mg of yellow oil is obtained, with a yield of 84%. 1 H NMR (400MHz, CDCl3) δ7.20–7.09(m,2H),6.61(dd,J=16.2,7.9Hz,3H),3.28(dt,J=7.1,2.1Hz,0.12H,94%D),2.77(t,J=2.0Hz,0.19H,94%D). 13 C NMR (100MHz, CDCl3) δ149.20,129.23,116.07,112.42,46.88–45.66(m),37.03–36.06(m),10.98.

[0058] Example 18, Preparation of Compound 18

[0059] The method is the same as Example 1, except that the amount of substrate is 0.4 mmol, methyl nicotinate (27 mg, 0.5 equivalent) is used instead of methyl benzoate, and the reaction time is 36 hours. 67 mg of yellow oil is obtained, with a yield of 84%. 1 H NMR (400MHz, CDCl3) δ7.24–7.15(m,2H),6.71–6.57(m,3H),3.40–3.27(m,0.19H),1.13(s,6H). 13 C NMR (100MHz, CDCl3) δ147.93,129.27,115.44,111.96,44.18–43.01(m),12.36.

[0060] Example 19, Preparation of Compound 19

[0061] The method is the same as Example 1, except that the amount of substrate is 0.4 mmol, methyl nicotinate (27 mg, 0.5 equivalent) is used instead of methyl benzoate, and the reaction time is 36 hours. 61 mg of light yellow oil is obtained, with a yield of 92%. 1 H NMR(400MHz, CDCl3)δ7.27–7.18(m,2H),6.92(dd,J=8.8,1.1Hz,2H),6.80(t, J=7.3Hz,1H),3.09(s,0.21H),1.75–1.64(m,4H),1.56(td,J=7.7,3.8Hz,2H). 13 C NMR (100MHz, CDCl3) δ152.26,129.08,119.15,116.48,50.57–49.41(m),25.66,24.32.

[0062] Example 20, Preparation of Compound 20

[0063] The method is the same as Example 1, except that the amount of substrate is 0.4 mmol, methyl nicotinate (27 mg, 0.5 equivalent) is used instead of methyl benzoate, and the reaction time is 36 hours. 67 mg of light yellow oil is obtained, with a yield of 99%. 1 H NMR (400MHz, CDCl3) δ7.27 (t, J = 8.0Hz, 2H), 6.88 (dd, J = 14.8, 7.7Hz, 3H), 3.83 (s, 4H), 3.12 (d, J = 5.3Hz, 0.21H). 13 C NMR (100MHz, CDCl3) δ151.33,129.24,120.02,115.67,66.83,49.31–48.05(m).

[0064] Example 21, Preparation of Compound 21

[0065] The method is the same as Example 1, except that the amount of substrate is 0.4 mmol, methyl nicotinate (27 mg, 0.5 equivalent) is used instead of methyl benzoate, and the reaction time is 36 hours. 55 mg of light yellow oil is obtained, with a yield of 92%. 1 H NMR (400MHz, CDCl3) δ7.25–7.17(m,2H),6.64(t,J=7.3Hz,1H),6.55(d,J=7.7Hz,2H),3.25–3.16(m,0.21H),1.95(s,4H). 13 C NMR (100MHz, CDCl3) δ151.33,129.24,120.02,115.67,66.83,49.24–48.11(m).

[0066] Example 22, Preparation of Compound 22

[0067] The method is the same as Example 1, except that the amount of substrate is 0.4 mmol, methyl nicotinate (27 mg, 0.5 equivalent) is used instead of methyl benzoate, and the reaction time is 36 hours. 38 mg of brown oil is obtained, with a yield of 91%. 1 H NMR(400MHz, CDCl3)δ7.07(d,J=6.1Hz,2H),6.78–6.58(m,1H),6.48(d,J=7.4Hz,1H),3.2 4(d,J=16.3Hz,0.08H,96%D),2.91(s,1.37H,32%D),2.72(dt,J=8.9,1.5Hz,1.08H,64%D). 13 C NMR (100MHz, CDCl3) δ153.50,130.37,127.39,124.34,117.86,107.32,55.47,36.51–35.56(m),28.61.

[0068] Example 23, Preparation of Compound 23

[0069] The method is the same as Example 1, except that the amount of substrate is 0.4 mmol, methyl nicotinate (27 mg, 0.5 equivalent) is used instead of methyl benzoate, and the reaction time is 36 hours. 47 mg of brown oil is obtained, with a yield of 91%. 1H NMR(400MHz, CDCl3)δ7.07(d,J=6.1Hz,2H),6.78–6.58(m,1H),6.48(d,J=7.4Hz,1H),3.2 4(d,J=16.3Hz,0.08H,96%D),2.91(s,1.37H,32%D),2.72(dt,J=8.9,1.5Hz,1.08H,64%D). 13 C NMR (100MHz, CDCl3) δ153.50,130.37,127.39,124.34,117.86,107.32,55.47,36.51–35.56(m),28.61.

[0070] Example 24, Preparation of Compound 24

[0071] The method is the same as Example 1, except that the amount of substrate is 0.4 mmol, methyl nicotinate (27 mg, 0.5 equivalent) is used instead of methyl benzoate, heavy water is (640 μL, 80 equiv), and the reaction time is 36 hours. 73 mg of brown oil is obtained with a yield of 97%. 1 H NMR (400MHz, CDCl3) δ7.24 (d, J = 8.4Hz, 2H), 6.45 (d, J = 8.4Hz, 2H), 3.45 (s, 1H), 2.74 (s, 0.11H). 13 C NMR (100MHz, CDCl3) δ148.35,131.88,113.98,108.73,29.76.

[0072] Example 25, Preparation of Compound 25

[0073] The method is the same as Example 1, except that the amount of substrate is 0.4 mmol, methyl nicotinate (55 mg, 1 equivalent) is used instead of methyl benzoate, and the reaction time is 36 hours. 45 mg of yellow oil is obtained with a yield of 82%. 1 H NMR (400MHz, CDCl3) δ6.95(t,J=8.5Hz,2H),6.59(t,J=7.4Hz,1H),6.45(d,J=7.9Hz,1H ),3.52(s,1H),3.25(t,0.1H,95%D),2.75(t,J=6.6Hz,1.71H,15%D),1.95–1.87(m,2H). 13CNMR(100MHz, CDCl3)δ144.80,129.55,126.77,121.51,116.98,114.25,41.97–40.90(m),26.96,22.00.

[0074] Example 26, Preparation of Compound 26

[0075] The method is the same as Example 1, except that the amount of substrate is 0.4 mmol, methyl nicotinate (55 mg, 1 equivalent) is used instead of methyl benzoate, heavy water is (640 μL, 80 equiv), and the reaction time is 48 hours. 60 mg of yellow solid is obtained with a yield of 88%. 1 H NMR (400MHz, CDCl3) δ7.23–7.14(m,3H),6.84(d,J=9.1Hz,2H),6.78(t,J=7.3Hz ,1H),3.12–2.97(m,0.79H,80%D),2.92(d,J=8.3Hz,2.58H,36%D),1.97(s,1H). 13 C NMR (100MHz, CDCl3) δ151.83, 129.13, 119.71, 116.06, 49.95, 46.00 (d, J = 9.2Hz).

[0076] Example 27, Preparation of Compound 27

[0077] The method is the same as Example 1, except that the amount of substrate is 0.4 mmol, methyl nicotinate (55 mg, 1 equivalent) is used instead of methyl benzoate, heavy water is (640 μL, 80 equiv), and the reaction time is 5 days. 31 mg of yellow solid is obtained with a yield of 57%. 1 HNMR (400MHz, CDCl3) δ7.29 (d, J=7.1Hz, 2H), 7.26–7.13 (m, 3H), 2.93 (s, 2H, 50%D), 2.50 (d, J=5.4Hz, 0.37H, 88%D). 13 C NMR (100MHz, CDCl3) 138.63, 128.69 (d, J = 6.9Hz), 126.55, 51.34, 34.52 (d, J = 3.5Hz).

[0078] Example 28, Preparation of Compound 28

[0079] The method is the same as Example 1, except that the amount of substrate is 0.4 mmol, methyl nicotinate (55 mg, 1 equivalent) is used instead of methyl benzoate, heavy water is (640 μL, 80 equiv), and the reaction time is 7 days. 61 mg of yellow solid is obtained, with a yield of 96%. 1 H NMR (400MHz, DMSO-d6) δ7.32(d,J=8.8Hz,2H),7.21(d,J=8.9Hz,2H),6.85(t,J=6.4Hz,0.79H,61%D),3.13(s,1.2H,40%D),2.68(d,J=6.8Hz,2H). 13 C NMR (100MHz, DMSO-d6) δ138.96, 131.13, 130.99, 128.60, 35.13 (d, J = 8.8Hz).

[0080] Example 29, Preparation of Compound 29

[0081] The method is the same as Example 1, except that the amount of substrate is 0.05 mmol, methyl nicotinate (27 mg, 1 equivalent) is used instead of methyl benzoate, heavy water is (320 μL, 80 equiv), and the reaction time is 7 days. 36 mg of yellow oil is obtained with a yield of 72%. 1 HNMR (400MHz, CDCl3) δ7.28(d,J=7.0Hz,2H),6.92(d,J=8.1Hz,2H),6.87(t,J=7.3Hz,1H),3.95–3.86(m,1H),3.84–3.74(m,1H),3.54 (dd, J=11.8, 3.9Hz, 1H), 3.26–3.15 (m, 0.53H, 87%D), 2.84 (s, 0.94H, 38%D), 2.75–2.56 (m, 1.93H, 38%D), 2.51–2.42 (m, 0.87H, 38%D). 13 CNMR (100MHz, CDCl3) δ150.98,129.20,120.05,116.16,66.96,64.86,60.36,53.23,48.33.

[0082] Example 30, Preparation of Compound 30

[0083] The method is the same as Example 1, except that the substrate is 0.05 mmol, methyl nicotinate (7 mg, 0.5 equivalent) is used instead of methyl benzoate, heavy water is (160 μL, 160 equiv), and the reaction time is 36 hours. 21 mg of yellow oil is obtained with a yield of 91%. 1HNMR (400MHz, CDCl3) δ6.91 (dd, J=8.4, 2.2Hz, 1H), 6.88–6.81 (m, 2H), 6.78 (d, J=8.1Hz, 1H), 6.68 (d, J= 7.7Hz,2H),3.87(dd,J=9.6,4.3Hz,12H),2.66(s,2H),2.51(q,J=11.8,9.8Hz,0.30H),2.45–2.31(m,0.2 4H, 92%D), 2.21 (d, J=7.6Hz, 0.26H), 2.10 (ddd, J=26.3, 13.4, 5.6Hz, 2H), 2.01 (s, 0.13H), 1.85 (td, J=1 2.9,4.5Hz,1H),1.53(dd,J=12.6,4.4Hz,1H),1.41(s,1H),1.18(d,J=6.7Hz,4H),0.79(d,J=6.7Hz,3H). 13 C NMR (100MHz, CDCl3) δ149.01,148.85,148.28,147.34,132.77,130.62,121.46,120.50,118.69,112 .02,111.26,111.09,55.99,55.92,55.88,55.85,53.37,37.95,35.52,32.74,29.70,22.91,18.61.

[0084] Example 31, Preparation of Compound 31

[0085] The method is the same as Example 1, except that the substrate is 0.1 mmol, methyl nicotinate (14 mg, 1 equivalent) is used instead of methyl benzoate, heavy water is (320 μL, 160 equiv), and the reaction time is 48 hours. 19 mg of yellow oil is obtained with a yield of 44%. 1 HNMR(400MHz, CDCl3)δ7.59(d,J=7.9Hz,1H),7.50(s,1H),7.47–7.34(m,3H),7.01(t,J=8.6Hz,2H),5.26–5.07(m,1.81H, 10%D), 2.22(ddt,J=27.9,10.5,5.7Hz,2.93H,27%D), 2.12(d,J=4.9Hz,0.26H,96%D), 1.43(ddd,J=40.7,11.6,4.6Hz,2H). 13CNMR(100MHz,CDCl3)δ163.29,160.84,149.36,140.26,131.92,126.79,126.71,12 5.23,122.81,118.63,115.49,115.27,111.78,91.07,71.32,44.81,38.75,21.46.

[0086] Example 32, Preparation of Compound 32

[0087] The method is the same as Example 1, except that the substrate is 0.2 mmol, methyl nicotinate (27 mg, 1 equivalent) is used instead of methyl benzoate, heavy water is (320 μL, 80 equiv), and the reaction time is 48 hours. 80 mg of yellow oil is obtained with a yield of 94%. 1 HNMR(400MHz, CDCl3)δ7.75–7.66(m,1H),7.51–7.41(m,4H),7.25(dd,J=8.6,5.0Hz,1H ),6.89(d,J=8.7Hz,2H),5.16(d,J=7.5Hz,1H),5.01(d,J=7.5Hz,1H),4.49–4.35(m,1H) ,3.81(s,3H),3.73(dt,J=13.6,4.5Hz,1H),2.71(ddd,J=15.1,7.4,4.3Hz,0.44H,57%D) ,2.47(ddd,J=19.1,9.2,4.9Hz,0.43H,57%D),2.30–2.22(m,3.24H,46%D),1.90(s,3H). 13 CNMR(100MHz,CDCl3)δ169.90,166.84,159.74,145.50,135.33,131.23,131.05,130.84,1 29.39,128.62,127.86,1274,126.71,124.74,113.73,71.09,55.22,54.36,53.43,20.51.

Claims

1. A class of α-deuterated amine compounds as shown in formula I, characterized in that The hydrogen on the adjacent carbon of N is deuterium, an isotope of hydrogen, and its general structural formula is as follows: Among them: R 1 , R 2 , R 3 and R 4 is aryl, substituted aryl, polycyclic aryl, heterocyclic aryl, substituted heterocyclic aryl, polycyclic aryl, C 1-18 Alkyl and C 1-10 Cycloalkyl, etc. The N atom may also be in a saturated aliphatic ring.

2. The compound of formula I as claimed in claim 1 includes but is not limited to the following compounds:

3. The method for preparing the α-deuterated amine compound according to claim 1-2, characterized in that The method comprises the following steps: Step 1: At room temperature, under an argon atmosphere, add amine (1, 0.2-0.4mmol, 1.0 equivalent), triisopropylsilanethiol (13uL, 30mol%), heavy water (40-80equiv), methyl benzoate (0.5-1.0equiv) and anhydrous ethyl acetate to the reaction tube. The substrate concentration is 0.2M. The solution is degassed by freeze-pump-thaw and then plugged with a rubber stopper. The reaction solution is stirred for a certain period of time under a 380nm LED. After the reaction is completed, the reaction solution is concentrated. In this step, the solvent can also be acetonitrile, acetone, 1,2-dichloroethane, dichloromethane, chloroform, ethyl acetate, methyl propionate, ethyl propionate, methyl formate, ethyl formate, or a mixed solvent of two of them. However, ester solvents are preferred. In this step, the wavelength of the light used can be any wavelength or band from 365nm to 450nm. However, any wavelength or waveband between 380nm and 400nm is preferred. In this step, the mercaptan used includes triphenylsilanethiol, triisopropylsilanethiol and phenylethylmercaptan, but triisopropylsilanethiol is preferred. Triisopropylsilanethiol has been fully H / D exchanged with heavy water before being added to the reaction solution. The reaction tube can be made of glass or quartz, but quartz is preferred. Step 2: After the reaction is completed, the reaction solution is concentrated and separated by column chromatography to obtain the target compound of formula I.

4. The α-deuterated amine compounds can be used for drug development and synthesis of other deuterated compounds.

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