Photocatalytic preparation method of deuterated acetamide compound

Abstract

The invention discloses a photocatalytic preparation method of a deuterated acetamide compound, and belongs to the technical field of synthesis of deuterated acetamide compounds. According to the technical scheme, the method is characterized in that a dichloroacetamide compound is used as a raw material, D2O is used as a deuterium source, and the dideuterated acetamide compound is synthesized through reaction under the room-temperature nitrogen illumination condition; according to the method, dichloroacetamide compounds are taken as raw materials, D2O is taken as a deuterium source, deuterated dichloroacetamide compounds are synthesized through room-temperature reaction, and monodeuterated or trideuterated acetamide compounds are respectively obtained through photocatalytic reaction according to different solvents (H2O or D2O) added into a system. The preparation method provided by the invention has the advantages of simple and safe operation, mild reaction conditions, no transition metal participation, cheap and easily available deuterium source, high deuteration rate, controllable number and the like.

Description

Technical Field

[0001] The present invention belongs to the technical field of the synthesis of deuterated acetamide compounds, and specifically relates to a photocatalytic preparation method for mono-deuterated, bis-deuterated, and tris-deuterated acetamide compounds. Background Art

[0002] The deuteration strategy replaces H atoms in the drug structure with D atoms, endowing the molecule with better pharmacokinetic properties, higher safety, and stereostability. With the listing of deuterated drugs such as deutetrabenazine, deucravacitinib, donafenib, and deuremidevir, the deuteration strategy has gradually become one of the most commonly used and efficient strategies in new drug research and development (Nat. Rev. Drug Discov., 2023, 22, 562–584; ChemMedChem 2024, e202400836.).

[0003] The acetamide moiety, as an important pharmacophore, is widely used in the research and development of drugs. For example, acetylcholine, paracetamol, linezolid, oseltamivir, etc. all contain this structure (Int. J. Chemtech Res, 2011, 3, 203-209.). Using the deuteration strategy to modify the structure of such drugs and synthesize deuterated acetamide derivatives is expected to improve pharmacokinetic properties and obtain new drug molecules by breaking through the original patented technology. Currently, the construction of tris-deuterated acetamide compounds can only be achieved by using expensive and hard-to-obtain deuterated acetic acid, and there is no effective synthesis method for the synthesis of mono-deuterated and bis-deuterated acetamide compounds, which greatly limits the research and development of such drugs. Therefore, developing a precise synthesis method for deuterated acetamide compounds with high efficiency, mild reaction conditions, high deuteration rate, and controllable number is of great significance for new drug research and development. Summary of the Invention

[0004] The technical problem solved by the present invention is to provide a photocatalytic preparation method for deuterated acetamide compounds that is simple and safe to operate, has mild reaction conditions, a high deuteration rate, and a controllable number, so as to solve the problems such as the shortage of synthesis methods for mono-deuterated and bis-deuterated acetamide compounds and the high cost of deuterium sources used in the synthesis method of tris-deuterated acetamide compounds.

[0005] The present invention adopts the following technical solution to solve the above technical problem: A photocatalytic preparation method for deuterated acetamide compounds, characterized in that: the same raw material dichloroacetamide is used to synthesize mono-deuterated acetamide compounds, bis-deuterated acetamide compounds, and tris-deuterated acetamide compounds;

[0006] The specific synthesis process of the bis-deuterated acetamide compounds is as follows: Under a nitrogen environment at room temperature, a dichloroacetamide compound, a photocatalyst, an additive, a solvent, and D2O are sequentially added to a reaction tube and subjected to a light reaction. After the reaction is completed, the reaction solution is extracted with ethyl acetate and saturated sodium chloride. After combining the organic phases, the solvent is evaporated, and the residue is purified by silica gel chromatography to obtain the bis-deuterated acetamide compounds;

[0007] The specific synthesis process of the mono-deuterated acetamide compounds is as follows: First, a dichloroacetamide compound, triethylamine (Et3N), acetonitrile (MeCN), and D2O are sequentially added to a reaction flask and reacted under a nitrogen environment at room temperature. After the reaction is completed, the reaction solution is extracted with ethyl acetate and saturated sodium chloride, and the organic phase is removed by rotary evaporation to obtain deuterated dichloroacetamide compounds; Then, under a nitrogen environment at room temperature, the deuterated dichloroacetamide compounds, a photocatalyst, an additive, a solvent, and H2O are sequentially added to a reaction tube and subjected to a light reaction. After the reaction is completed, the reaction solution is extracted with ethyl acetate and saturated sodium chloride, the solvent is evaporated, and the residue is purified by silica gel chromatography to obtain the mono-deuterated acetamide compounds;

[0008] The specific synthesis process of the tri-deuterated acetamide compounds is as follows: First, a dichloroacetamide compound, Et3N, MeCN, and D2O are added to a reaction flask and reacted under a nitrogen environment at room temperature. After the reaction is completed, the reaction solution is extracted with ethyl acetate and saturated sodium chloride, and the organic phase is removed by rotary evaporation to obtain deuterated dichloroacetamide compounds; Then, under a nitrogen environment at room temperature, the deuterated dichloroacetamide compounds, a photocatalyst, an additive, a solvent, and D2O are sequentially added to a reaction tube and subjected to a light reaction. After the reaction is completed, the reaction solution is extracted with ethyl acetate and saturated sodium chloride, the solvent is evaporated, and the residue is purified by silica gel chromatography to obtain the tri-deuterated acetamide compounds;

[0009] The structural formula of the dichloroacetamide compounds is shown in Formula A, the structural formula of the bis-deuterated acetamide compounds is shown in Formula B, the structural formula of the deuterated dichloroacetamide compounds is shown in Formula C, the structural formula of the mono-deuterated acetamide compounds is shown in Formula D, and the structural formula of the tri-deuterated acetamide compounds is shown in Formula E:

[0010]

[0011] In Formula A, Formula B, Formula C, Formula D, and Formula E, R is phenyl, substituted phenyl, pyridine, benzyl, alkyl, tetrahydroisoquinoline, amino acid, dipeptide, drug, or natural product, and the substituents on the benzene ring of the substituted phenyl are hydroxyl, C 1～5 alkyl, C 1～2 alkoxy, trifluoromethyl, ester group, phenyl, F, Cl, or Br.

[0012] Further defined, the structural formula of the bis-deuterated acetamide compounds is:

[0013]

[0014] The structural formula of the mono-deuterated acetamide compound is as follows:

[0015]

[0016] The structural formula of the tri-deuterated acetamide compound is as follows:

[0017]

[0018] Further defined, the deuterated acetamide compound is a mono-deuterated, di-deuterated, and tri-deuterated derivative of a drug (paracetamol, phenacetin, and linezolid) or a health product (melatonin), and its structural formula is:

[0019]

[0020] Further defined, the specific synthesis route of the di-deuterated acetamide compound is:

[0021]

[0022] The specific synthesis route of the mono-deuterated acetamide compound is:

[0023]

[0024] The specific synthesis route of the tri-deuterated acetamide compound is:

[0025]

[0026] Further defined, the photocatalytic reaction conditions in the synthesis process of the deuterated acetamide compound are to react for 12 h under room temperature and nitrogen conditions, and the light source used in the photochemical reaction is an LED lamp with a wavelength of 405 nm and a power of 10 W.

[0027] Further defined, the photocatalyst is one or more of rhodamine B, rhodamine 6G, eosin Y, rose bengal, fluorescein, methylene blue, sodium fluorescein, and 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile (4CzIPN), and preferably 4CzIPN, and its structural formula is:

[0028]

[0029] Further defined, the additive is one or more of triethylamine, N,N-diisopropylethylamine, tetramethylethylenediamine, triethylenediamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, and lithium hydroxide, and preferably triethylamine.

[0030] Further defined, the solvent is one or more of acetonitrile, tetrahydrofuran, N,N-dimethylacetamide, methanol, N-methylpyrrolidone, N,N-dimethylformamide, 2-methyltetrahydrofuran, dimethyl carbonate, dichloromethane, toluene, dimethyl sulfoxide, 1,4-dioxane and polyethylene glycol, preferably acetonitrile.

[0031] Further defined, in the synthesis process of the bis-deuterated acetamide compound, the molar ratio of the dichloroacetamide compound, the photocatalyst and the additive is 1:0.01-0.1:1-5, preferably 1:0.05:2;

[0032] In the synthesis process of the mono-deuterated acetamide compound, the molar ratio of the deuterated dichloroacetamide compound, the photocatalyst and the additive is 1:0.01-0.1:1-5, preferably 1:0.05:2;

[0033] In the synthesis process of the tris-deuterated acetamide compound, the molar ratio of the deuterated dichloroacetamide compound, the photocatalyst and the additive is 1:0.01-0.1:1-5, preferably 1:0.05:2.

[0034] Compared with the prior art, the present invention has the following advantages and beneficial effects: The present invention provides a preparation method of mono-deuterated, bis-deuterated and tris-deuterated acetamide compounds. Compared with the prior art, the preparation method of the present invention fills the blank of the synthesis of mono-deuterated and bis-deuterated acetamide compounds and solves the problem that there is no synthesis method for such compounds. In the synthesis process of the tris-deuterated acetamide compound, cheap deuterated water is used as the deuterium source, avoiding the use of expensive deuterated acetic anhydride in the traditional method. The preparation method of the present invention has the advantages of simple and safe operation, mild reaction conditions, no participation of transition metals, cheap and easily available deuterium source, high deuteration rate and controllable number, etc. Under the mediation of visible light, mono-deuterated, bis-deuterated and tris-deuterated acetamide compounds are obtained respectively by adjusting the synthesis conditions using the same raw material. Detailed implementation manners

[0035] Example 1

[0036] In a 10 mL reaction tube equipped with a magnetic stir bar, 2,2-dichloro-N-phenylacetamide (0.2 mmol) and 4CzIPN (5 mol%) were added. Under a nitrogen atmosphere at room temperature, D2O (0.2 mL), Et3N (2.0 equiv), and anhydrous MeCN (2 mL) were added. Subsequently, the reaction was carried out under irradiation with a 10 W 405 nm LED for 12 hours. After the reaction was completed, the reaction mixture was quenched with saturated aqueous NaCl solution (5 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure using a rotary evaporator. The residue was purified by silica gel chromatography to obtain the target product, which was a yellow solid with a yield of 88% and a deuterium incorporation rate of 99%.

[0037] The structural formula of the target product is as follows:

[0038] The yellow solid was analyzed by NMR spectroscopy and mass spectrometry, and the data are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.53–7.49 (m, 3H), 7.30 (m, 2H), 7.12–7.07 (m, 1H), 2.19–2.08 (m, 1H). 13 C NMR (150 MHz, CDCl3) δ 168.7, 138.1, 129.1, 124.4, 120.1, 24.8–23.9 (m). 2 HNMR (61 MHz, CHCl3) δ 2.18–2.12 (m). HRMS Calcd for C8H8D2NO [M+H] + : m / z 138.0882, Found: 138.0885。

[0039] Example 2

[0040] Under the same conditions as in Example 1, 2,2-dichloro-N-(o-tolyl)acetamide was used to replace 2,2-dichloro-N-phenylacetamide as the raw material. The finally obtained target product was a white solid with a yield of 93% and a deuterium incorporation rate of 98%.

[0041] The structural formula of the target product is as follows:

[0042] The white solid was analyzed by NMR spectroscopy and mass spectrometry, and the data are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 7.6 Hz, 1H), 7.21–7.17 (m, 2H), 7.09–7.06 (m, 2H), 2.25 (s, 3H), 2.21–2.12 (m, 1H). 1313C NMR (150 MHz, CDCl3) δ 168.6, 135.8, 130.6, 129.7, 126.8, 125.5, 123.7, 24.2–23.6 (m), 17.9. 2 1H NMR (61 MHz, CHCl3) δ 2.21–2.15 (m). HRMS Calcd for C9H 10 D2NO [M+H] + : m / z 152.1039, Found: 152.1038。

[0043] Example 3

[0044] Under the same conditions as in Example 1, the raw material 2,2-dichloro-N-(p-tolyl)acetamide was used to replace 2,2-dichloro-N-phenylacetamide. The finally obtained target product was a yellow solid with a yield of 85% and a deuteration rate of 98%.

[0045] The structural formula of the target product is as follows:

[0046] The nuclear magnetic spectroscopy and mass spectrometry analysis of the above yellow solid gave the following data: 1 1H NMR (400 MHz, CDCl3) δ 7.59 (s, 1H), 7.37 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 2.30 (s, 3H), 2.13–2.10 (m, 1H). 13 13C NMR (100 MHz, CDCl3) δ 168.7, 135.5, 134.0, 129.5, 120.3, 24.5–23.7 (m), 21.0. 2 1H NMR (61 MHz, CHCl3) δ 2.16–2.12 (m). HRMS Calcd for C9H 10 D2NO [M+H] + : m / z 152.1039, Found: 152.1039。

[0047] Example 4

[0048] Under the same conditions as in Example 1, the raw material 2,2-dichloro-N-(m-tolyl)acetamide was used to replace 2,2-dichloro-N-phenylacetamide. The finally obtained target product was a yellow solid with a yield of 68% and a deuteration rate of 97%.

[0049] The structural formula of the target product is as follows:

[0050] The nuclear magnetic spectroscopy and mass spectrometry analysis of the above yellow solid gave the following data: 11H NMR (600 MHz, CDCl3) δ 7.37–7.35 (m, 2H), 7.27–7.26f (m, 1H), 7.19 (t, J = 7.8 Hz, 1H), 6.92 (d, J = 7.2 Hz, 1H), 2.32 (s, 3H), 2.16–2.12 (m, 1H). 13 13C NMR (150 MHz, CDCl3) δ 168.6, 139.0, 137.9, 128.9, 125.3, 120.7, 117.1, 24.5–21.6 (m), 21.6. 2 1H NMR (61 MHz, CHCl3) δ 2.17–2.14 (m). HRMS Calcd for C9H 10 D2NO [M+H] + : m / z 152.1039, Found: 152.1039。

[0051] Example 5

[0052] Under the same conditions as in Example 1, 2,2-dichloro-N-(4-butylphenyl)acetamide was used to replace 2,2-dichloro-N-phenylacetamide as the raw material. The finally obtained target product was a yellow oil, with a yield of 61% and a deuteration rate of 97%.

[0053] The structural formula of the target product is as follows:

[0054] The nuclear magnetic spectroscopy and mass spectrometry analysis of the above yellow oil are as follows: 1 1H NMR (400 MHz, CDCl3) δ 7.43–7.38 (m, 3H), 7.11 (d, J = 8.0 Hz, 2H), 2.56 (t, J = 7.6 Hz, 2H), 2.15–2.12 (m, 1H), 1.60–1.53 (m, 2H), 1.38–1.29 (m, 2H), 0.93 - 0.89 (m, 3H). 13 13C NMR (150 MHz, CDCl3) δ 168.5, 139.2, 135.6, 129.0, 120.2, 35.2, 33.8z, 24.6–24.0 (m), 22.4, 14.1. 2 1H NMR (61 MHz, CHCl3) δ 2.16–2.13 (m). HRMS Calcd for C 12 H 16 D2NO [M+H] + : m / z 194.1509, Found: 194.1509。

[0055] Example 6

[0056] Under the same conditions as in Example 1, 2,2-dichloro-N-(4-ethylphenyl)acetamide was used to replace 2,2-dichloro-N-phenylacetamide as the raw material. The finally obtained target product was a yellow solid with a yield of 86% and a deuteration rate of 96%.

[0057] The structural formula of the target product is as follows:

[0058] The nuclear magnetic resonance spectrum and mass spectrum of the above yellow solid were analyzed, and the data are as follows: 1 H NMR(400MHz,CDCl3)δ7.60(s,1H),7.40(d,J = 8.0Hz,2H),7.13(d,J = 8.0Hz,2H),2.60(q,J = 7.6Hz,2H),2.14–2.12(m,1H),1.21(t,J = 7.6Hz,3H). 13 C NMR(150MHz,CDCl3)δ168.8,140.5,135.6,128.4,120.4,28.4,24.5–23.8(m),15.7. 2 H NMR(61MHz,CHCl3)δ2.16–2.12(m).HRMS Calcd forC 10 H 12 D2NO[M + H] + :m / z 166.1196,Found:166.1196。

[0059] Example 7

[0060] Under the same conditions as in Example 1, 2,2-dichloro-N-(4-tert-butylphenyl)acetamide was used to replace 2,2-dichloro-N-phenylacetamide as the raw material. The finally obtained target product was a yellow solid with a yield of 75% and a deuteration rate of 93%.

[0061] The structural formula of the target product is as follows:

[0062] The nuclear magnetic resonance spectrum and mass spectrum of the above yellow solid were analyzed, and the data are as follows: 1 H NMR(600MHz,CDCl3)δ7.63(s,1H),7.42(d,J = 7.8Hz,2H),7.32(d,J = 7.8Hz,2H),2.14–2.12(m,1H),1.29(s,9H). 13 C NMR(150MHz,CDCl3)δ168.7,147.4,135.4,125.9,120.0,34.5,31.5,24.5–23.8(m).2 1H NMR (61 MHz, CHCl3) δ 2.17–2.13 (m). HRMS Calcd for C 12 H 16 D2NO [M + H] + : m / z 194.1509, Found: 194.1505。

[0063] Example 8

[0064] Under the same conditions as in Example 1, the raw material 2,2-dichloro-N-(o-ethylphenyl)acetamide was used to replace 2,2-dichloro-N-phenylacetamide. The finally obtained target product was a white solid with a yield of 62% and a deuteration rate of 94%.

[0065] The structural formula of the target product is as follows:

[0066] The nuclear magnetic resonance spectroscopy and mass spectrometry analysis of the above white solid were carried out, and the data are as follows: 1 1H NMR (600 MHz, CDCl3) δ 7.70 (d, J = 7.8 Hz, 1H), 7.29 (m, 1H), 7.20 (m, 2H), 7.13 (t, J = 7.8 Hz, 1H), 2.61–2.57 (m, 2H), 2.19–2.16 (m, 1H), 1.22 (t, J = 7.8 Hz, 3H). 13 13C NMR (150 MHz, CDCl3) δ 168.8, 135.6, 135.0, 128.7, 126.7, 125.9, 124.4, 24.35, 24.4, 24.6–23.9 (m), 14.1. 2 1H NMR (61 MHz, CHCl3) δ 2.25–2.22 (m). HRMS Calcd for C 10 H 12 D2NO [M + H] + : m / z 166.1196, Found: 166.1199。

[0067] Example 9

[0068] Under the same conditions as in Example 1, the raw materials 2,2-dichloro-N-(o-ethylphenyl)acetamide and 2,2-dichloro-N-(3,5-dimethylphenyl)acetamide were used to replace 2,2-dichloro-N-phenylacetamide. The finally obtained target product was a yellow solid with a yield of 76% and a deuteration rate of 96%.

[0069] The structural formula of the target product is as follows:

[0070] The above yellow solid was analyzed by NMR spectroscopy and mass spectrometry, and the data are as follows: 1 H NMR(400MHz,CDCl3)δ7.35(s,1H),7.12(s,2H),6.74(s,1H),2.28(s,6H),2.14–2.12(m,1H). 13 C NMR(150MHz,CDCl3)δ168.6,138.8,137.8,126.2,117.8,24.7–24.2(m),21.5. 2 H NMR(61MHz,CHCl3)δ2.17–2.11(m).HRMS Calcd for C 10 H 12 D2NO[M+H] + :m / z 166.1196,Found:166.1190。

[0071] Example 10

[0072] Under the same conditions as in Example 1, 2,2-dichloro-N-(2,6-dimethylphenyl)acetamide was used to replace 2,2-dichloro-N-phenylacetamide as the raw material. The finally obtained target product was a yellow solid with a yield of 75% and a deuteration rate of 91%.

[0073] The structural formula of the target product is as follows:

[0074] The above yellow solid was analyzed by NMR spectroscopy and mass spectrometry, and the data are as follows: 1 H NMR(400MHz,CDCl3)δ7.18–7.04(m,3H),6.87(s,1H),2.27(s,2H),2.22(s,4H),2.19–2.15(m,1H). 13 C NMR(150MHz,DMSO-d6)δ168.3,135.9,135.6,128.1,126.7,22.9–22.3(m),18.6. 2 H NMR(61MHz,CHCl3)δ2.22–2.15(m).HRMS Calcd for C 10 H 12 D2NO[M+H] + :m / z 166.1196,Found:166.1194。

[0075] Example 11

[0076] Under the same conditions as in Example 1, the raw material 2,2-dichloro-N-phenylacetamide was replaced with 2,2-dichloro-N-(4-methoxyphenyl)acetamide, and the finally obtained target product was a yellow solid with a yield of 63% and a deuteration rate of 94%.

[0077] The structural formula of the target product is as follows:

[0078] The above yellow solid was subjected to nuclear magnetic spectroscopy and mass spectrometry analysis, and the data are as follows: 1 H NMR(600MHz,CDCl3)δ7.46(s,1H),7.38(d,J=9.0Hz,2H),6.83(d,J=8.4Hz,2H),3.77(s,3H),2.13–2.10(m,1H). 13 C NMR(150MHz,CDCl3)δ168.6,156.6,131.1,122.1,114.2,55.6,24.4–23.8(m). 2 HNMR(61MHz,CHCl3)δ2.15–2.12(m).HRMS Calcd for C9H 10 D2NO2[M+H] + :m / z168.0989,Found:168.0988。

[0079] Example 12

[0080] Under the same conditions as in Example 1, the raw material 2,2-dichloro-N-phenylacetamide was replaced with 2,2-dichloro-N-([1,1'-biphenyl]-2-yl)acetamide, and the finally obtained target product was a yellow solid with a yield of 71% and a deuteration rate of 98%.

[0081] The structural formula of the target product is as follows:

[0082] The above yellow solid was subjected to nuclear magnetic spectroscopy and mass spectrometry analysis, and the data are as follows: 1 H NMR(600MHz,CDCl3)δ8.25(d,J=8.4Hz,1H),7.48(t,J=7.8Hz,2H),7.43–7.40(m,1H),7.38–7.35(m,3H),7.26–7.23(m,1H),7.18–7.15(m,1H),7.14(s,1H),2.01–1.98(m,1H). 1313C NMR (150 MHz, CDCl3) δ 168.4, 138.3, 134.8, 132.4, 130.3, 129.4, 129.2, 128.5, 128.1, 124.5, 121.8, 24.6–24.1 (m). 2 1H NMR (61 MHz, CHCl3) δ 2.04–1.98 (m). HRMS Calcd for C 14 H 12 D2NO[M + H] + : m / z 214.1196, Found: 214.1190。

[0083] Example 13

[0084] Under the same conditions as in Example 1, the raw material 2,2-dichloro-N-phenylacetamide was replaced with methyl 4-(2,2-dichloroacetamido)benzoate, and the finally obtained target product was a yellow solid with a yield of 60% and a deuteration rate of 100%.

[0085] The structural formula of the target product is as follows:

[0086] The nuclear magnetic resonance spectroscopy and mass spectrometry analysis of the above yellow solid were carried out, and the data are as follows: 1 1H NMR (600 MHz, CDCl3) δ 7.98 (d, J = 8.4 Hz, 2H), 7.89 (s, 1H), 7.60 (d, J = 8.4 Hz, 2H), 3.89 (s, 3H), 2.19–2.16 (m, 1H). 13 13C NMR (150 MHz, CDCl3) δ 169.0, 166.8, 142.4, 130.9, 125.6, 119.0, 52.2, 24.7–24.1 (m). 2 1H NMR (61 MHz, CHCl3) δ 2.22–2.14 (m). HRMS Calcd for C 10 H 10 D2NO3[M + H] + : m / z 196.0938, Found: 196.0938。

[0087] Example 14

[0088] Under the same conditions as in Example 1, the raw material 2,2-dichloro-N-phenylacetamide was replaced with 2,2-dichloro-N-(4-fluorophenyl)acetamide, and the finally obtained target product was a yellow solid with a yield of 65% and a deuteration rate of 99%.

[0089] The structural formula of the target product is as follows:

[0090] The above yellow solid was analyzed by nuclear magnetic resonance spectroscopy and mass spectrometry, and the data are as follows: 1 H NMR(600MHz,CDCl3)δ7.56(s,1H),7.44(dd,J=8.4,4.8Hz,2H),6.99(t,J=8.4Hz,2H),2.18–2.08(m,1H). 13 CNMR(150MHz,CDCl3)δ168.6,159.5(d,J=243.4Hz),134.0(d,J=2.8Hz),122.0(d,J=7.8Hz),115.7(d,J=22.1Hz),24.4–23.7(m). 19 F NMR(565MHz,CDCl3)δ-118.0. 2 H NMR(61MHz,CHCl3)δ2.16–2.10(m).HRMS Calcd for C8H7D2FNO[M+H] + :m / z156.0789,Found:156.0789。

[0091] Example 15

[0092] Under the same conditions as in Example 1, 2,2-dichloro-N-(4-chlorophenyl)acetamide was used to replace 2,2-dichloro-N-phenylacetamide as the raw material. The finally obtained target product was a yellow solid with a yield of 78% and a deuteration rate of 100%.

[0093] The structural formula of the target product is as follows:

[0094] The above yellow solid was analyzed by nuclear magnetic resonance spectroscopy and mass spectrometry, and the data are as follows: 1 H NMR(400MHz,CDCl3)δ7.45(d,J=8.8Hz,2H),7.32(s,1H),7.27(d,J=8.4Hz,2H),2.17–2.14(m,1H). 13 C NMR(150MHz,DMSO-d6)δ169.1,138.7,129.0,127.0,121.0,24.3–23.5(m). 2 H NMR(61MHz,CHCl3)δ2.17–2.10(m).HRMS Calcd for C8H7D2ClNO[M+H] + :m / z 172.0493,Found:172.0493。

[0095] Example 16

[0096] Under the same conditions as in Example 1, 2,2-dichloro-N-(4-bromophenyl)acetamide was used to replace 2,2-dichloro-N-phenylacetamide as the raw material. The finally obtained target product was a yellow solid, with a yield of 90% and a deuteration rate of 99%.

[0097] The structural formula of the target product is as follows:

[0098] The above yellow solid was analyzed by nuclear magnetic spectroscopy and mass spectrometry, and the data are as follows: 1 H NMR(400MHz,CDCl3)δ7.41(s,4H),7.37(s,1H),2.16–2.13(m,1H). 13 C NMR(150MHz,CDCl3)δ168.5,137.1,132.1,121.5,117.0,24.6–23.9(m). 2 H NMR(61MHz,CHCl3)δ2.16–2.09(m).HRMS Calcd forC8H7D2BrNO[M+H] + :m / z 215.9988,Found:215.9985。

[0099] Example 17

[0100] Under the same conditions as in Example 1, 2,2-dichloro-N-(4-fluoro-3-methylphenyl)acetamide was used to replace 2,2-dichloro-N-phenylacetamide as the raw material. The finally obtained target product was a yellow solid, with a yield of 76% and a deuteration rate of 95%.

[0101] The structural formula of the target product is as follows:

[0102] The above yellow solid was analyzed by nuclear magnetic spectroscopy and mass spectrometry, and the data are as follows: 1 H NMR(400MHz,CDCl3)δ7.53(s,1H),7.34–7.32(m,1H),7.23–7.20(m,1H),6.91(t,J=9.0Hz,1H),2.22(s,3H),2.14–2.11(m,1H). 13 C NMR(150MHz,CDCl3)δ168.7,158.1(d,J=242.1Hz),133.6(d,J=3.0Hz),125.4(d,J=18.6Hz),123.5(d,J=4.6Hz),119.3(d,J=8.5Hz),115.2(d,J=23.4Hz),24.5–23.7(m),14.75(d,J=3.3Hz). 1919F NMR (565 MHz, CDCl3) δ -122.3. 2 1H NMR (61 MHz, CHCl3) δ 2.16–2.10 (m). HRMS Calcd for C9H9D2FNO [M+H] + : m / z 170.0945, Found: 170.0945.

[0103] Example 18

[0104] Under the same conditions as in Example 1, 2,2-dichloro-N-(o-fluorophenyl)acetamide was used to replace 2,2-dichloro-N-phenylacetamide as the raw material. The finally obtained target product was a yellow solid with a yield of 72% and a deuteration rate of 97%.

[0105] The structural formula of the target product is as follows:

[0106] The nuclear magnetic spectroscopy and mass spectrometry analysis of the above yellow solid gave the following data: 1 1H NMR (400 MHz, CDCl3) δ 8.29 (t, J = 7.8 Hz, 1H), 7.40 (s, 1H), 7.12 (t, J = 7.8 Hz, 1H), 7.09–7.02 (m, 2H), 2.22–2.19 (m, 1H). 13 13C NMR (150 MHz, CDCl3) δ 168.5, 152.4 (d, J = 242.8 Hz), 126.5 (d, J = 9.9 Hz), 124.7 (d, J = 4.1 Hz), 124.4 (d, J = 7.7 Hz), 122.0, 114.9 (d, J = 19.4 Hz), 24.7–24.1 (m). 19 19F NMR (565 MHz, CDCl3) δ -131.5. 2 1H NMR (61 MHz, CHCl3) δ 2.24–2.21 (m). HRMS Calcd for C8H7D2FNO [M+H] + : m / z 156.0789, Found: 156.0790.

[0107] Example 19

[0108] Under the same conditions as in Example 1, 2,2-dichloro-N-(o-chlorophenyl)acetamide was used to replace 2,2-dichloro-N-phenylacetamide as the raw material. The finally obtained target product was a yellow solid with a yield of 65% and a deuteration rate of 100%.

[0109] The structural formula of the target product is as follows:

[0110] The above yellow solid was analyzed by NMR spectroscopy and mass spectrometry, and the data are as follows: 1 H NMR(400MHz,CDCl3)δ8.36(d,J=9.0Hz,1H),7.62(s,1H),7.36(d,J=8.4Hz,1H),7.28–7.25(m,1H),7.04(t,J=7.8Hz,1H),2.25–2.21(m,1H). 13 C NMR(150MHz,CDCl3)δ168.4,134.7,129.1,127.9,124.7,122.7,121.8,25.0–24.4(m). 2 H NMR(61MHz,CHCl3)δ2.28–2.22(m).HRMS Calcd forC8H7D2ClNO[M+H] + :m / z 172.0493,Found:172.0492。

[0111] Example 20

[0112] Under the same conditions as in Example 1, 2,2-dichloro-N-(m-fluorophenyl)acetamide was used to replace 2,2-dichloro-N-phenylacetamide as the raw material. The finally obtained target product was a yellow solid with a yield of 79% and a deuteration rate of 99%.

[0113] The structural formula of the target product is as follows:

[0114] The above yellow solid was analyzed by NMR spectroscopy and mass spectrometry, and the data are as follows: 1 HNMR(600MHz,CDCl3)δ7.75(s,1H),7.47(d,J=10.8Hz,1H),7.23(q,J=7.8Hz,1H),7.14(d,J=8.4Hz,1H),6.80–6.77(m,1H),2.17–2.14(m,1H). 13 C NMR(150MHz,CDCl3)δ169.1,163.1(d,J=244.4Hz),139.6(d,J=10.9Hz),130.1(d,J=9.0Hz),115.3(d,J=2.8Hz),111.1(d,J=21.2Hz),107.5(d,J=26.3Hz),24.4–23.6(m). 19 F NMR(376MHz,DMSO-d6)δ-116.3(q,J=8.5Hz). 21H NMR(61MHz,CHCl3)δ2.18–2.13(m).HRMS Calcd for C8H7D2FNO[M+H] + :m / z 156.0789,Found:156.0788。

[0115] Example 21

[0116] Under the same conditions as in Example 1, 2,2-dichloro-N-(m-chlorophenyl)acetamide was used to replace 2,2-dichloro-N-phenylacetamide as the raw material. The finally obtained target product was a yellow solid with a yield of 75% and a deuteration rate of 99%.

[0117] The structural formula of the target product is as follows:

[0118] The nuclear magnetic spectroscopy and mass spectrometry analysis of the above yellow solid were carried out, and the data are as follows: 1 1H NMR(400MHz,CDCl3)δ7.69(s,1H),7.62(s,1H),7.34(d,J = 8.4Hz,1H),7.23–7.14(m,1H),7.07(d,J = 8.4Hz,1H),2.17–2.14(m,1H). 13 13C NMR(150MHz,CDCl3)δ168.9,139.2,134.7,130.1,124.5,120.1,118.0,24.6–23.8(m). 2 1H NMR(61MHz,CHCl3)δ2.17–2.14(m).HRMS Calcd for C8H7D2ClNO[M+H] + :m / z 172.0493,Found:172.0494。

[0119] Example 22

[0120] Under the same conditions as in Example 1, 2,2-dichloro-N-(m-bromophenyl)acetamide was used to replace 2,2-dichloro-N-phenylacetamide as the raw material. The finally obtained target product was a yellow solid with a yield of 50% and a deuteration rate of 99%.

[0121] The structural formula of the target product is as follows:

[0122] The nuclear magnetic spectroscopy and mass spectrometry analysis of the above yellow solid were carried out, and the data are as follows: 11H NMR (600 MHz, CDCl3) δ 7.76 (s, 1H), 7.50 (s, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 7.16 (t, J = 7.8 Hz, 1H), 2.17–2.14 (m, 1H). 13 13C NMR (150 MHz, CDCl3) δ 168.7, 139.3, 130.4, 127.4, 122.9, 122.7, 118.4, 24.7–24.1 (m). 2 1H NMR (61 MHz, CHCl3) δ 2.18–2.12 (m). HRMS Calcd for C8H7D2BrNO [M+H] + : m / z 215.9988, Found: 215.9989。

[0123] Example 23

[0124] Under the same conditions as in Example 1, 2,2-dichloro-N-(p-trifluoromethylphenyl)acetamide was used to replace 2,2-dichloro-N-phenylacetamide as the raw material. The finally obtained target product was a yellow solid with a yield of 80% and a deuteration rate of 99%.

[0125] The structural formula of the target product is as follows:

[0126] The nuclear magnetic spectroscopy and mass spectrometry analysis of the above yellow solid were carried out, and the data are as follows: 1 1H NMR (600 MHz, CDCl3) δ 7.63 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H), 7.50 (s, 1H), 2.21–2.18 (m, 1H). 13 13C NMR (150 MHz, DMSO-d6) δ 169.5, 143.3, 126.5 (q, J = 3.8 Hz), 124.9 (d, J = 271.2 Hz), 123.5 (q, J = 31.9 Hz), 119.3, 24.5–23.8 (m). 19 19F NMR (565 MHz, CDCl3) δ -62.1. 2 1H NMR (61 MHz, CHCl3) δ 2.21–2.14 (m). HRMS Calcd for C9H7D2F3NO [M+H] + : m / z 206.0757, Found: 206.0755。

[0127] Example 24

[0128] Under the same conditions as in Example 1, the raw material 2,2-dichloro-N-phenylacetamide was replaced with 2,2-dichloro-N-(3,5-difluorophenyl)acetamide, and the finally obtained target product was a yellow solid with a yield of 70% and a deuteration rate of 100%.

[0129] The structural formula of the target product is as follows:

[0130] The above yellow solid was subjected to nuclear magnetic spectroscopy and mass spectrometry analysis, and the data are as follows: 1 H NMR(600MHz,CDCl3)δ7.59(s,1H),7.12(d,J=7.2Hz,2H),6.57–6.52(m,1H),2.18–2.15(m,1H). 13 C NMR(150MHz,CDCl3)δ168.8,163.3(dd,J=246.5,14.4Hz),140.1(t,J=13.2Hz),102.9–102.7(m),99.6(t,J=25.8Hz),24.7–24.0(m). 19 F NMR(376MHz,CDCl3)δ-108.8. 2 H NMR(61MHz,CHCl3)δ2.18–2.13(m).HRMS Calcd for C8H6D2F2NO[M+H] + :m / z174.0694,Found:174.0694。

[0131] Example 25

[0132] Under the same conditions as in Example 1, the raw material 2,2-dichloro-N-phenylacetamide was replaced with 2,2-dichloro-N-(3-chloro-4-fluorophenyl)acetamide, and the finally obtained target product was a yellow solid with a yield of 71% and a deuteration rate of 98%.

[0133] The structural formula of the target product is as follows:

[0134] The above yellow solid was subjected to nuclear magnetic spectroscopy and mass spectrometry analysis, and the data are as follows: 1 H NMR(600MHz,CDCl3)δ7.67(dd,J=6.6,3.0Hz,1H),7.58(s,1H),7.31–7.29(m,1H),7.07–7.04(m,1H),2.16–2.12(m,1H). 1313C NMR (150 MHz, CDCl3) δ 168.7, 154.9 (d, J = 246.3 Hz), 134.6 (d, J = 3.3 Hz), 122.4, 121.2 (d, J = 18.6 Hz), 119.8 (d, J = 6.8 Hz), 116.7 (d, J = 22.0 Hz), 24.4–23.8 (m). 19 19F NMR (565 MHz, CDCl3) δ -120.5. 2 1H NMR (61 MHz, CHCl3) δ 2.17–2.14 (m). HRMS Calcd for C8H6D2ClFNO [M+H] + : m / z 190.0399, Found: 190.0396。

[0135] Example 26

[0136] Under the same conditions as in Example 1, the raw material 2,2-dichloro-N-phenylacetamide was replaced with N-benzyl-2,2-dichloroacetamide, and the finally obtained target product was a yellow solid with a yield of 85% and a deuteration rate of 97%.

[0137] The structural formula of the target product is as follows:

[0138] The above yellow solid was subjected to nuclear magnetic spectroscopy and mass spectrometry analysis, and the data are as follows: 1 1H NMR (600 MHz, CDCl3) δ 7.33–7.31 (m, 2H), 7.28–7.26 (m, 3H), 6.03 (s, 1H), 4.40 (d, J = 5.4 Hz, 2H), 2.00–1.97 (m, 1H). 13 13C NMR (150 MHz, CDCl3) δ 170.1, 138.4, 128.8, 127.9, 127.6, 43.8, 23.3–22.6 (m). 2 1H NMR (61 MHz, CHCl3) δ 2.04–1.98 (m). HRMS Calcd for C9H 10 D2NO [M+H] + : m / z 152.1039, Found: 152.1039。

[0139] Example 27

[0140] Under the same conditions as in Example 1, the raw material 2,2-dichloro-N-phenylacetamide was replaced with 2,2-dichloro-N-propylacetamide, and the finally obtained target product was a yellow oil with a yield of 55% and a deuteration rate of 98%.

[0141] The structural formula of the target product is as follows:

[0142] The above yellow oil was subjected to nuclear magnetic spectroscopy and mass spectrometry analysis, and the data are as follows: 1 H NMR(400MHz,CDCl3)δ5.71(s,1H),3.21–3.15(m,2H),1.96–1.92(m,1H),1.55–1.45(m,2H),0.92–0.88(m,3H). 13 CNMR(150MHz,CDCl3)δ170.3,41.5,23.3–22.7(m),22.9,11.5. 2 H NMR(61MHz,CHCl3)δ2.01–1.97(m).HRMS Calcd for C5H 10 D2NO[M+H] + :m / z 104.1039,Found:104.1039。

[0143] Example 28

[0144] Under the same conditions as in Example 1, 2,2-dichloro-N-(pyridin-2-yl)acetamide was used to replace 2,2-dichloro-N-phenylacetamide as the raw material. The finally obtained target product was a yellow solid with a yield of 54% and a deuteration rate of 100%.

[0145] The structural formula of the target product is as follows:

[0146] The above yellow solid was subjected to nuclear magnetic spectroscopy and mass spectrometry analysis, and the data are as follows: 1 H NMR(600MHz,CDCl3)δ8.72(s,1H),8.26(d,J=4.8Hz,1H),8.21(d,J=7.8Hz,1H),7.72–7.69(m,1H),7.05–7.02(m,1H),2.20–2.17(m,1H). 13 C NMR(150MHz,CDCl3)δ169.0,151.7,147.7,138.7,119.9,114.4,24.7–24.2(m). 2 H NMR(61MHz,CHCl3)δ2.27–2.22(m).HRMS Calcd for C7H7D2N2O[M+H] + :m / z 139.0835,Found:139.0835。

[0147] Example 29

[0148] Under the same conditions as in Example 1, 2,2-dichloro-N-(4-hydroxyphenyl)acetamide was used to replace 2,2-dichloro-N-phenylacetamide as the raw material. The finally obtained target product was a yellow solid with a yield of 61% and a deuteration rate of 99%.

[0149] The structural formula of the target product is as follows:

[0150] The above yellow solid was analyzed by nuclear magnetic spectroscopy and mass spectrometry, and the data are as follows: 1 H NMR(600MHz,DMSO-d6)δ9.63(s,1H),9.13(s,1H),7.33(d,J=9.0Hz,2H),6.66(d,J=9.0Hz,2H),1.97–1.94(m,1H). 13 C NMR(150MHz,DMSO-d6)δ168.1,153.6,131.5,121.3,115.5,24.1–23.6(m). 2 H NMR(61MHz,CHCl3)δ1.45–1.40(m).HRMS Calcd for C8H8D2NO2[M+H] + :m / z154.0832,Found:154.0831。

[0151] Example 30

[0152] Under the same conditions as in Example 1, 2,2-dichloro-N-(4-ethoxyphenyl)acetamide was used to replace 2,2-dichloro-N-phenylacetamide as the raw material. The finally obtained target product was a yellow solid with a yield of 70% and a deuteration rate of 97%.

[0153] The structural formula of the target product is as follows:

[0154] The above yellow solid was analyzed by nuclear magnetic spectroscopy and mass spectrometry, and the data are as follows: 1 H NMR(600MHz,CDCl3)δ7.46(s,1H),7.36(d,J=9.0Hz,2H),6.82(d,J=9.0Hz,2H),4.01–3.97(m,2H),2.12–2.09(m,1H),1.40–1.37(m,3H). 13 C NMR(150MHz,CDCl3)δ168.6,155.9,131.0,122.1,114.8,63.8,24.4–23.6(m),14.9. 2 H NMR(61MHz,CHCl3)δ2.15–2.10(m).HRMS Calcd forC10 H 12 D2NO2[M+H] + : m / z 182.1145, Found: 182.1148。

[0155] Example 31

[0156] Under the same conditions as in Example 1, the raw material 2,2-dichloro-N-(6-methylpyridin-2-yl)acetamide was used to replace 2,2-dichloro-N-phenylacetamide. The finally obtained target product was a yellow oil, with a yield of 82% and a deuteration rate of 99%.

[0157] The structural formula of the target product is as follows:

[0158] The nuclear magnetic resonance spectrum and mass spectrum of the above yellow oil were analyzed, and the data are as follows: 1 H NMR(400MHz, CDCl3)δ8.11(s, 1H), 7.98(d, J = 8.4Hz, 1H), 7.60–7.57(m, 1H), 6.88(d, J = 7.2Hz, 1H), 2.44(s, 3H). 13 C NMR(150MHz, CDCl3)δ168.8, 156.8, 150.7, 138.9, 119.4, 110.9, 24.6–24.0(m). 2 HNMR(61MHz, CDCl3)δ2.15–2.11(m). HRMS Calcd for C8H9D2N2O[M+H] + : m / z153.0992, Found: 153.0990。

[0159] Example 32

[0160] Under the same conditions as in Example 1, the raw material 2,2-dichloro-1-(3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one was used to replace 2,2-dichloro-N-phenylacetamide. The finally obtained target product was a yellow oil, with a yield of 79% and a deuteration rate of 99%.

[0161] The structural formula of the target product is as follows:

[0162] The nuclear magnetic resonance spectrum and mass spectrum of the above yellow oil were analyzed, and the data are as follows: 1 H NMR(400MHz, CDCl3)δ7.24–7.06(m, 4H), 4.76–4.56(m, 2H), 3.85–3.64(m, 2H), 2.94–2.80(m, 2H), 2.18–2.14(m, 1H). 1313C NMR (150 MHz, CDCl3) δ 169.75 (m), 135.95–131.52 (m), 128.74 (m), 127.07, 126.78 (m), 126.68, 126.33 (m), 49.01–38.77 (m), 29.10 (m), 22.01–20.76 (m). 2 1H NMR (61 MHz, CDCl3) δ 2.23–2.18 (m). HRMS Calcd for C 11 H 12 D2NO [M + H] + : m / z 178.1196, Found: 178.1199。

[0163] Example 33

[0164] Under the same conditions as in Example 1, the raw material 2,2-dichloro-N-phenylacetamide was replaced with 2,2-dichloro-N-(((1R,4aS,10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthren-1-yl)methyl)acetamide. The finally obtained target product was a yellow oil, with a yield of 75% and a deuteration rate of 97%.

[0165] The structural formula of the target product is as follows:

[0166] The nuclear magnetic spectroscopy and mass spectrometry analysis of the above yellow oil gave the following data: 1 1H NMR (400 MHz, CDCl3) δ 7.17 (d, J = 8.0 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.90 (s, 1H), 5.53–5.49 (m, 1H), 3.26–3.20 (m, 1H), 3.11–3.06 (m, 1H), 2.95–2.78 (m, 3H), 2.29 (d, J = 12.8 Hz, 1H), 2.06–2.05 (m, 1H), 1.97–1.94 (m, 1H), 1.92–1.86 (m, 1H), 1.80–1.64 (m, 3H), 1.44–1.35 (m, 3H), 1.26–1.22 (m, 9H), 0.94 (s, 3H). 13 13C NMR (150 MHz, CDCl3) δ 170.3, 147.3, 145.8, 134.9, 127.1, 124.3, 124.0, 49.9, 45.3, 38.4, 37.6, 37.4, 36.3, 33.5, 30.3, 25.4, 24.11, 24.07, 23.7–23.1 (m), 19.0, 18.9, 18.7.2 1H NMR (61 MHz, CHCl3) δ 1.20–1.96 (m). HRMS Calcd for C 22 H 32 D2NO[M + H] + : m / z 330.2761, Found: 330.2762。

[0167] Example 34

[0168] Under the same conditions as in Example 1, the raw material was replaced with methyl (2,2-dichloroacetyl)-L-leucine instead of 2,2-dichloro-N-phenylacetamide. The finally obtained target product was a yellow oil, with a yield of 89% and a deuteration rate of 98%.

[0169] The structural formula of the target product is as follows:

[0170] The nuclear magnetic resonance spectrum and mass spectrum of the above yellow oil were analyzed, and the data are as follows: 1 1H NMR (400 MHz, CDCl3) δ 6.02 (d, J = 7.6 Hz, 1H), 4.65–4.59 (m, 1H), 3.71 (s, 3H), 2.00–1.96 (m, 1H), 1.67–1.58 (m, 2H), 1.55–1.46 (m, 1H), 0.92 (dd, J = 6.4, 2.4 Hz, 7H). 13 13C NMR (150 MHz, CDCl3) δ 173.9, 170.1, 52.4, 50.8, 41.8, 25.0, 22.9, 23.1–22.5 (m), 22.1. 2 1H NMR (61 MHz, CHCl3) δ 2.06–2.03 (m). HRMS Calcd for C9H 16 D2NO3[M + H] + : m / z 190.1407, Found: 190.1402。

[0171] Example 35

[0172] Under the same conditions as in Example 1, the raw material was replaced with benzyl (2,2-dichloroacetyl)-L-phenylalaninate instead of 2,2-dichloro-N-phenylacetamide. The finally obtained target product was a white solid, with a yield of 78% and a deuteration rate of 98%.

[0173] The structural formula of the target product is as follows:

[0174] The nuclear magnetic resonance spectrum and mass spectrum of the above white solid were analyzed, and the data are as follows: 11H NMR (400 MHz, CDCl3) δ 7.39–7.34 (m, 3H), 7.31–7.29 (m, 2H), 7.23–7.21 (m, 3H), 7.01–7.00 (m, 2H), 6.01 (d, J = 7.8 Hz, 1H), 5.18–5.11 (m, 2H), 4.95–4.92 (m, 1H), 3.11 (ddd, J = 12.0, 6.0 Hz, 2H), 1.97–1.94 (m, 1H). 13 13C NMR (150 MHz, CDCl3) δ 171.7, 169.8, 135.8, 135.2, 129.4, 128.7, 128.7, 128.7, 128.7, 127.2, 67.4, 53.2, 37.9, 23.1–22.5 (m). 2 1H NMR (61 MHz, CHCl3) δ 2.00–1.93 (m). HRMS Calcd for C 18 H 18 D2NO3 [M+H] + : m / z 300.1564, Found: 300.1564。

[0175] Example 36

[0176] Under the same conditions as in Example 1, the raw material methyl (2,2-dichloroacetyl)-L-phenylalanine-L-leucine was used to replace 2,2-dichloro-N-phenylacetamide, and the finally obtained target product was a yellow solid with a yield of 87% and a deuteration rate of 100%.

[0177] The structural formula of the target product is as follows:

[0178] The above yellow solid was subjected to nuclear magnetic spectroscopy and mass spectrometry analysis, and the data are as follows: 1 1H NMR (600 MHz, CDCl3) δ 7.29–7.26 (m, 2H), 7.24–7.20 (m, 3H), 6.55 (d, J = 7.8 Hz, 1H), 6.49 (d, J = 8.4 Hz, 1H), 4.76–4.72 (m, 1H), 4.53–4.49 (m, 1H), 3.69 (s, 3H), 3.09–3.02 (m, 2H), 1.95–1.92 (m, 1H), 1.61–1.52 (m, 2H), 1.50–1.45 (m, 1H), 0.88 (d, J = 6.0 Hz, 6H). 1313C NMR (150 MHz, CDCl3) δ 172.8, 171.1, 170.2, 136.6, 129.5, 128.7, 127.1, 54.4, 52.4, 51.0, 41.4, 38.5, 24.8, 22.8, 23.1–22.4 (m), 22.00. 2 1H NMR (61 MHz, CHCl3) δ 1.99–1.92 (m). HRMS Calcd for C 18 H 25 D2N2O4 [M+H] + : m / z 337.2091, Found: 337.2092。

[0179] Example 37

[0180] Under the same conditions as in Example 1, the raw material (2,2-dichloroacetyl) glyceryl-L-leucine methyl ester was used to replace 2,2-dichloro-N-phenylacetamide. The finally obtained target product was a yellow oil, with a yield of 48% and a deuterium substitution rate of 98%.

[0181] The structural formula of the target product is as follows:

[0182] The nuclear magnetic spectroscopy and mass spectrometry analysis of the above yellow oil were carried out, and the data are as follows: 1 1H NMR (400 MHz, CDCl3) δ 7.06 (d, J = 8.0 Hz, 1H), 6.76 (t, J = 5.2 Hz, 1H), 4.58–4.53 (m, 1H), 4.03–3.92 (m, 2H), 3.71 (s, 3H), 2.02–1.98 (m, 1H), 1.70–1.52 (m, 3H), 0.93–0.90 (m, 6H). 13 13C NMR (150 MHz, CDCl3) δ 173.4, 171.1, 169.3, 52.5, 51.0, 43.3, 41.2, 24.9, 22.9, 22.76–22.4 (m), 21.8. 2 1H NMR (61 MHz, CHCl3) δ 2.09–2.03 (m). HRMS Calcd for C 11 H 19 D2N2O4 [M+H] + : m / z 247.1622, Found: 247.1620。

[0183] Example 38

[0184] Under the same conditions as in Example 1, the raw material (2,2-dichloroacetyl) glyceryl-L-phenylalanine benzyl ester was used to replace 2,2-dichloro-N-phenylacetamide. The finally obtained target product was a yellow solid with a yield of 55% and a deuteration rate of 97%.

[0185] The structural formula of the target product is as follows:

[0186] The above yellow solid was analyzed by NMR spectroscopy and mass spectrometry, and the data are as follows: 1 H NMR(600MHz,CDCl3)δ7.37–7.32(m,3H),7.29–7.27(m,2H),7.23–7.20(m,3H),7.03–7.01(m,2H),6.85(d,J=6.5Hz,1H),6.55–6.53(m,1H),5.26(q,J=12.0Hz,2H),4.89–4.85(m,1H),3.91–3.82(m,2H),3.14–3.04(m,2H),1.96–1.93(m,1H). 13 C NMR(150MHz,CDCl3)δ171.3,170.9,168.9,135.7,135.1,129.4,128.7,128.7,128.7,128.6,127.3,67.4,53.4,43.2,37.9,22.8–22.3(m). 2 H NMR(61MHz,CHCl3)δ2.02–1.96(m).HRMS Calcd for C 20 H 21 D2N2O4[M+H] + :m / z357.1778,Found:357.1778。

[0187] Example 39

[0188] Under the same conditions as in Example 1, the raw material (S)-2,2-dichloro-N-((3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide was used to replace 2,2-dichloro-N-phenylacetamide. The finally obtained target product was a yellow solid with a yield of 76% and a deuteration rate of 100%.

[0189] The structural formula of the target product is as follows:

[0190] The above yellow solid was analyzed by NMR spectroscopy and mass spectrometry, and the data are as follows: 11H NMR (400 MHz, CDCl3) δ 7.39 (dd, J = 14.4, 2.6 Hz, 1H), 7.04–7.01 (m, 1H), 6.88 (t, J = 9.2 Hz, 1H), 6.81–6.77 (m, 1H), 4.78–4.71 (m, 1H), 4.01–3.96 (m, 1H), 3.84–3.82 (m, 4H), 3.76–3.71 (m, 1H), 3.63–3.60 (m, 2H), 3.02–2.99 (m, 4H), 1.98–1.94 (m, 1H). 13 13C NMR (150 MHz, CDCl3) δ 171.5, 155.49 (d, J = 246.0 Hz), 154.6, 136.6 (d, J = 9.0 Hz), 133.0 (d, J = 10.5 Hz), 118.9 (d, J = 3.0 Hz), 114.0 (d, J = 3.0 Hz), 107.6 (d, J = 10.5 Hz), 72.1, 67.0, 51.0 (d, J = 3.0 Hz), 47.7, 41.9, 22.9–22.2 (m). 19 19F NMR (376 MHz, CDCl3) δ -120.1. 2 1H NMR (61 MHz, CHCl3) δ 1.29 (br, s). HRMS Calcd for C 16 H 19 D2FN3O4 [M + H] + : m / z 340.1637, Found: 340.1639。

[0191] Example 40

[0192] Under the same conditions as in Example 1, 2,2-dichloro-N-(2-(5-methoxy-1H-indol-3-yl)ethyl)acetamide was used to replace 2,2-dichloro-N-phenylacetamide as the raw material. The finally obtained target product was a yellow solid with a yield of 59% and a deuteration rate of 95%.

[0193] The structural formula of the target product is as follows:

[0194] The nuclear magnetic spectroscopy and mass spectrometry analysis of the above yellow solid gave the following data: 11H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.27–7.24 (m, 1H), 7.01 (dd, J = 14.4, 2.4 Hz, 2H), 6.86 (dd, J = 8.8, 2.4 Hz, 1H), 5.65 (s, 1H), 3.85 (s, 3H), 3.58 (q, J = 6.4 Hz, 2H), 2.95–2.91 (m, 2H), 1.92–1.88 (m, 1H). 13 13C NMR (150 MHz, CDCl3) δ 170.4, 154.2, 131.7, 127.9, 123.0, 112.7, 112.5, 112.2, 100.6, 56.1, 39.9, 25.4, 23.5–22.7 (m). 2 1H NMR (61 MHz, CHCl3) δ 1.26–1.23 (m). HRMS Calcd for C 13 H 15 D2N2O2 [M + H] + : m / z 235.1411, Found: 235.1410。

[0195] Example 41

[0196] Preparation method of 2,2-dichloro-N-phenylacetamide-2-d: In a 10 mL reaction tube equipped with a magnetic stir bar, add 2,2-dichloro-N-phenylacetamide (0.2 mmol). Under a nitrogen atmosphere at room temperature, add D2O (0.2 mL), Et3N (2.0 equiv), and MeCN (2 mL), and then stir at room temperature for 12 hours. After the reaction is completed, quench the reaction mixture with saturated NaCl aqueous solution (5 mL), and extract with ethyl acetate (3 × 10 mL). Dry the combined organic layers over anhydrous Na2SO4, and evaporate the solvent under reduced pressure using a rotary evaporator to obtain the compound 2,2-dichloro-N-phenylacetamide-2-d as a white solid with a yield of 96% and a deuteration rate of 99%.

[0197] In a 10 mL reaction tube equipped with a magnetic stir bar, add 2,2-dichloro-N-phenylacetamide-2-d (0.2 mmol) and 4CzIPN (5 mol%). Under a nitrogen atmosphere at room temperature, add H2O (0.2 mL), Et3N (2.0 equiv), and anhydrous MeCN (2 mL), and then react under irradiation with a 10 W 405 nm LED for 12 hours. After the reaction is completed, quench the reaction mixture with saturated NaCl aqueous solution (5 mL), and extract with ethyl acetate (3 × 10 mL). Dry the combined organic layers over anhydrous Na2SO4, and evaporate the solvent under reduced pressure using a rotary evaporator. The residue is purified by silica gel column chromatography to obtain the target product as a white solid with a yield of 92% and a deuteration rate of 99%.

[0198] The structural formula of the target product is as follows:

[0199] The white solid above was analyzed by nuclear magnetic spectroscopy and mass spectrometry, and the data are as follows: 1 H NMR(600MHz,CDCl3)δ7.62(s,1H),7.50(d,J=7.8Hz,2H),7.30(t,J=7.8Hz,2H),7.09(t,J=7.2Hz,1H),2.16–2.14(m,2H). 13 C NMR(150MHz,CDCl3)δ168.8,138.1,129.1,124.4,120.1,24.6–24.3(m). 2 HNMR(61MHz,CHCl3)δ2.22–2.14(m).HRMS Calcd for C8H9DNO[M+H] + :m / z 137.0820,Found:137.0822。

[0200] Example 42

[0201] Under the same conditions as in Example 41, 2,2-dichloro-N-(o-tolyl)acetamide was used to replace 2,2-dichloro-N-phenylacetamide as the raw material. The finally obtained target product was a white solid with a yield of 88% and a deuteration rate of 99%.

[0202] The structural formula of the target product is as follows:

[0203] The white solid above was analyzed by nuclear magnetic spectroscopy and mass spectrometry, and the data are as follows: 1 H NMR(400MHz,CDCl3)δ7.70(d,J=8.0Hz,1H),7.24–7.12(m,3H),7.09–7.05(m,1H),2.24(s,3H),2.17–2.15(m,2H). 13 C NMR(150MHz,CDCl3)δ168.6,135.7,130.6,129.8,126.8,125.5,123.8,24.3–23.9(m),17.9. 2 H NMR(61MHz,CHCl3)δ2.36–2.29(m).HRMS Calcd for C9H 11 DNO[M+H] + :m / z151.0977,Found:151.0979。

[0204] Example 43

[0205] Under the same conditions as in Example 41, the raw material 2,2-dichloro-N-phenylacetamide was replaced with N-(4-bromophenyl)-2,2-dichloroacetamide, and the finally obtained target product was a white solid with a yield of 84% and a deuteration rate of 97%.

[0206] The structural formula of the target product is as follows:

[0207] The nuclear magnetic resonance spectrum and mass spectrum of the above white solid were analyzed, and the data are as follows: 1 H NMR(400MHz,CDCl3)δ7.54(s,1H),7.40(s,4H),2.16–2.14(m,2H). 13 C NMR(150MHz,CDCl3)δ168.5,137.1,132.1,121.5,117.0,24.8–24.4(m). 2 H NMR(61MHz,CHCl3)δ2.20–2.13(m).HRMS Calcd forC8H8DBrNO[M+H] + :m / z 214.9925,Found:214.9928。

[0208] Example 44

[0209] Under the same conditions as in Example 41, the raw material 2,2-dichloro-N-phenylacetamide was replaced with N-([1,1'-biphenyl]-2-yl)-2,2-dichloroacetamide, and the finally obtained target product was a white solid with a yield of 74% and a deuteration rate of 97%.

[0210] The structural formula of the target product is as follows:

[0211] The nuclear magnetic resonance spectrum and mass spectrum of the above white solid were analyzed, and the data are as follows: 1 H NMR(400MHz,CDCl3)δ8.26(d,J=8.0Hz,1H),7.51–7.47(m,2H),7.43(d,J=7.2Hz,1H),7.40–7.35(m,3H),7.24(d,J=6.8Hz,1H),7.20–7.14(m,2H),2.02–2.00(m,2H). 13 C NMR(150MHz,CDCl3)δ168.4138.3,134.8,132.3,130.2,129.4,129.2,128.5,128.1,124.5,121.8,24.7–24.3(m). 21H NMR (61 MHz, CHCl3) δ 2.08–2.01 (m). HRMS Calcd for C 14 H 13 DNO [M+H] + : m / z 213.1133, Found: 213.1133。

[0212] Example 45

[0213] Under the same conditions as in Example 41, 2,2-dichloro-N-(4-(trifluoromethyl)phenyl)acetamide was used to replace 2,2-dichloro-N-phenylacetamide as the raw material. The finally obtained target product was a white solid with a yield of 86% and a deuteration rate of 95%.

[0214] The structural formula of the target product is as follows:

[0215] The nuclear magnetic spectroscopy and mass spectrometry analysis of the above white solid were carried out, and the data are as follows: 1 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 8.8 Hz, 2H), 7.56 (d, J = 8.8 Hz, 2H), 7.53 (s, 1H), 2.20–2.19 (m, 2H). 13 13C NMR (150 MHz, CDCl3) δ 168.8, 141.1, 126.4 (q, J = 3.2 Hz), 126.2 (d, J = 33.2 Hz), 124.2 (d, J = 271.7 Hz), 119.5, 24.8–24.6 (m). 19 19F NMR (565 MHz, CDCl3) δ -62.1. 2 1H NMR (61 MHz, CHCl3) δ 2.25–2.17 (m). HRMS Calcd for C9H8DF3NO [M+H] + : m / z 205.0694, Found: 205.0697。

[0216] Example 46

[0217] Under the same conditions as in Example 41, 2,2-dichloro-N-(p-hydroxyphenyl)acetamide was used to replace 2,2-dichloro-N-phenylacetamide as the raw material. The finally obtained target product was a white oil with a yield of 76% and a deuteration rate of 97%.

[0218] The structural formula of the target product is as follows:

[0219] The nuclear magnetic spectroscopy and mass spectrometry analysis of the above white oil were carried out, and the data are as follows: 11H NMR (600 MHz, DMSO-d6) δ 9.65 (s, 1H), 9.13 (s, 1H), 7.34–7.31 (m, 2H), 6.68–6.65 (m, 2H), 1.97–1.95 (m, 2H). 13 13C NMR (150 MHz, CDCl3) δ 168.0, 153.6, 131.5, 121.3, 115.5, 24.2–23.8 (m). 2 1H NMR (61 MHz, CHCl3) δ 2.16–2.08 (m). HRMS Calcd for C8H9DNO2 [M+H] + : m / z 153.0769, Found: 153.0767。

[0220] Example 47

[0221] Under the same conditions as in Example 41, the raw material 2,2-dichloro-N-(p-ethoxyphenyl)acetamide was used to replace 2,2-dichloro-N-phenylacetamide. The finally obtained target product was a white solid with a yield of 78% and a deuteration rate of 95%.

[0222] The structural formula of the target product is as follows:

[0223] The nuclear magnetic spectroscopy and mass spectrometry analysis of the above white solid were carried out, and the data are as follows: 1 1H NMR (400 MHz, CDCl3) δ 7.63 (s, 1H), 7.38–7.34 (m, 2H), 6.83–6.79 (m, 2H), 4.01–3.95 (m, 2H), 2.11–2.09 (m, 2H), 1.40–1.36 (m, 3H). 13 13C NMR (150 MHz, CDCl3) δ 168.7, 155.9, 131.1, 122.1, 114.8, 63.8, 24.3–23.9 (m), 14.9. 2 1H NMR (61 MHz, CHCl3) δ 2.19–2.12 (m). HRMS Calcd for C 10 H 13 DNO2 [M+H] + : m / z 181.1082, Found: 181.1082。

[0224] Example 48

[0225] Under the same conditions as in Example 41, the raw material was replaced with benzyl (2,2-dichloroacetyl)-L-phenylpropionate in place of 2,2-dichloro-N-phenylacetamide. The finally obtained target product was a white solid with a yield of 84% and a deuteration rate of 95%.

[0226] The structural formula of the target product is as follows:

[0227] The above white solid was subjected to nuclear magnetic spectroscopy and mass spectrometry analysis, and the data are as follows: 1 H NMR(400MHz,CDCl3)δ7.38–7.35(m,3H),7.32–7.29(m,2H),7.23–7.22(m,3H),7.03–6.98(m,2H),5.99(d,J=8.0Hz,1H),5.13(dd,J=12.0,8.0Hz,2H),4.94(dt,J=8.0,5.8Hz,1H),3.16–3.07(m,2H),1.98–1.96(m,2H). 13 C NMR(150MHz,CDCl3)δ171.6,169.7,135.8,135.1,129.4,128.7,128.7,128.7,128.6,127.2,67.4,53.2,37.9,23.2–22.8(m). 2 H NMR(61MHz,CHCl3)δ2.05–1.97(m).HRMS Calcd for C 18 H 19 DNO3[M+H] + :m / z 299.1501,Found:299.1503。

[0228] Example 49

[0229] Under the same conditions as in Example 41, the raw material was replaced with 2,2-dichloro-N-(2-(5-methoxy-1H-indol-3-yl)ethyl)acetamide in place of 2,2-dichloro-N-phenylacetamide. The finally obtained target product was a yellow solid with a yield of 76% and a deuteration rate of 99%.

[0230] The structural formula of the target product is as follows:

[0231] The above yellow solid was subjected to nuclear magnetic spectroscopy and mass spectrometry analysis, and the data are as follows: 11H NMR (400 MHz, CDCl3) δ 8.24 (s, 1H), 7.26–7.24 (m, 1H), 7.03–6.99 (m, 2H), 6.88–6.84 (m, 1H), 5.64 (s, 1H), 3.85 (s, 3H), 3.60–3.55 (m, 2H), 2.95–2.91 (m, 2H), 1.92 (s, 2H). 13 13C NMR (150 MHz, CDCl3) δ 170.3, 154.2, 131.7, 127.9, 123.0, 112.7, 112.5, 112.2, 100.6, 56.1, 39.9, 25.4, 23.5–23.1 (m). 2 1H NMR (61 MHz, CHCl3) δ 1.98–1.94 (m). HRMS Calcd for C 13 H 16 DN2O2 [M+H] + : m / z 234.1348, Found: 234.1344。

[0232] Example 50

[0233] Under the same conditions as in Example 41, the raw material (S)-2,2-dichloro-N-((3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide was used to replace 2,2-dichloro-N-phenylacetamide. The finally obtained target product was a yellow solid with a yield of 83% and a deuteration rate of 100%.

[0234] The structural formula of the target product is as follows:

[0235] The above yellow solid was subjected to nuclear magnetic spectroscopy and mass spectrometry analysis, and the data are as follows: 1 1H NMR (400 MHz, CDCl3) δ 7.43–7.38 (m, 1H), 7.30–7.27 (m, 1H), 7.09–7.06 (m, 1H), 6.94–6.89 (m, 1H), 4.83–4.76 (m, 1H), 4.07–4.02 (m, 3H), 3.87–3.85 (m, 4H), 3.80–3.71 (m, 2H), 3.68–3.61 (m, 1H), 3.06–3.03 (m, 4H). 1313C NMR (150 MHz, CDCl3) δ 167.4, 155.5 (d, J = 246.0 Hz), 154.3, 136.7 (d, J = 9.0 Hz), 132.9 (d, J = 10.4 Hz), 118.9 (d, J = 4.2 Hz), 114.1 (d, J = 3.2 Hz), 107.7 (d, J = 26.4 Hz), 71.6, 67.0, 51.0 (d, J = 2.8 Hz), 47.8, 42.6, 42.6–42.1 (m). 19 19F NMR (376 MHz, CDCl3) δ -120.0. 2 1H NMR (61 MHz, CHCl3) δ 3.42–3.31 (m). HRMS Calcd for C 16 H 20 DFN3O4 [M+H] + : m / z 339.1574, Found: 339.1577。

[0236] Example 51

[0237] Preparation method of 2,2-dichloro-N-phenylacetamide-2-d: In a 10 mL reaction tube equipped with a stir bar, add 2,2-dichloro-N-phenylacetamide (0.2 mmol), and add D2O (0.2 mL), Et3N (2.0 equiv.) and MeCN (2 mL) under a nitrogen atmosphere at room temperature. Then stir at room temperature for 12 hours. After the reaction is completed, quench the reaction mixture with saturated NaCl aqueous solution (5 mL), and extract with ethyl acetate (3 × 10 mL). Dry the combined organic layers with anhydrous Na2SO4, and evaporate the solvent under reduced pressure using a rotary evaporator to obtain the compound 2,2-dichloro-N-phenylacetamide-2-d as a white solid with a yield of 96% and a deuteration rate of 99%.

[0238] In a 10 mL reaction tube equipped with a stir bar, add 2,2-dichloro-N-phenylacetamide-2-d (0.2 mmol) and 4CzIPN (5 mol%), and add D2O (0.2 mL), Et3N (2.0 equiv.) and anhydrous MeCN (2 mL) under a nitrogen atmosphere at room temperature. Then react under irradiation with a 10 W 405 nm LED for 12 hours. After the reaction is completed, quench the reaction mixture with saturated NaCl aqueous solution (5 mL), and extract with ethyl acetate (3 × 10 mL). Dry the combined organic layers with anhydrous Na2SO4, and evaporate the solvent under reduced pressure using a rotary evaporator. The residue is purified by silica gel chromatography to obtain the target product, which is a white solid with a yield of 92% and a deuteration rate of 93%.

[0239] The structural formula of the target product is as follows:

[0240] The above white solid was analyzed by NMR spectroscopy and mass spectrometry, and the data are as follows: 1 H NMR(400MHz,CDCl3)δ7.50(d,J=8.0Hz,2H),7.44(s,1H),7.33–7.28(m,2H),7.12–7.08(m,1H). 13 C NMR(150MHz,CDCl3)δ168.7,138.0,129.1,124.4,120.1,24.3–23.8(m). 2 H NMR(61MHz,CHCl3)δ2.18(br,s).HRMS Calcd for C8H7D3NO[M+H] + :m / z 139.0946,Found:139.0946。

[0241] Example 52

[0242] Under the same conditions as in Example 51, 2,2-dichloro-N-(m-tolyl)acetamide was used as the raw material to replace 2,2-dichloro-N-phenylacetamide. The finally obtained target product was a white solid with a yield of 92% and a deuteration rate of 92%.

[0243] The structural formula of the target product is as follows:

[0244] The above white solid was analyzed by NMR spectroscopy and mass spectrometry, and the data are as follows: 1 H NMR(600MHz,CDCl3)δ7.68(d,J=7.8Hz,1H),7.19–7.16(m,3H),7.08–7.06(m,1H),2.23(s,3H). 13 C NMR(150MHz,CDCl3)δ168.7,135.7,130.6,129.9,126.8,125.5,123.9,23.9–23.3(m),17.9. 2 H NMR(61MHz,CHCl3)δ2.19(br,s).HRMS Calcd for C9H9D3NO[M+H] + :m / z153.1102,Found:153.1107。

[0245] Example 53

[0246] Under the same conditions as in Example 51, 2,2-dichloro-N-(p-bromophenyl)acetamide was used as the raw material to replace 2,2-dichloro-N-phenylacetamide. The target product was a white solid with a yield of 83% and a deuteration rate of 94%.

[0247] The structural formula of the target product is as follows:

[0248] The above white solid was subjected to nuclear magnetic resonance spectroscopy and mass spectrometry analysis, and the data are as follows: 1 H NMR(400MHz,CDCl3)δ7.41(s,4H),7.31(s,1H). 13 C NMR(150MHz,CDCl3)δ168.5,137.1,132.1,121.5,117.0,24.4–23.9(m). 2 H NMR(61MHz,CHCl3)δ2.15(br,s).HRMS Calcd for C8H6D3BrNO[M+H] + :m / z217.0051,Found:217.0055。

[0249] Example 54

[0250] Under the same conditions as in Example 51, the raw material 2,2-dichloro-N-phenylacetamide was replaced with N-([1,1'-biphenyl]-2-yl)-2,2-dichloroacetamide, and the finally obtained target product was a white solid with a yield of 81% and a deuteration rate of 92%.

[0251] The structural formula of the target product is as follows:

[0252] The above white solid was subjected to nuclear magnetic resonance spectroscopy and mass spectrometry analysis, and the data are as follows: 1 H NMR(400MHz,CDCl3)δ8.26(d,J=8.0Hz,1H),7.51–7.47(m,2H),7.43(d,J=7.2Hz,1H),7.39–7.35(m,3H),7.24(d,J=7.2Hz,1H),7.18(t,J=7.6Hz,1H),7.14(s,1H). 13 C NMR(150MHz,CDCl3)δ168.4,138.3,134.8,132.3,130.2,129.4,129.2,128.6,128.1,124.5,121.8,24.5–23.9(m). 2 HNMR(61MHz,CHCl3)δ2.02(br,s).HRMS Calcd for C 14 H 11 D3NO[M+H] + :m / z215.1259,Found:215.1259。

[0253] Example 55

[0254] Under the same conditions as in Example 51, 2,2-dichloro-N-(p-trifluoromethylphenyl)acetamide was used to replace 2,2-dichloro-N-phenylacetamide as the raw material. The finally obtained target product was a white solid with a yield of 82% and a deuteration rate of 93%.

[0255] The structural formula of the target product is as follows:

[0256] The white solid was analyzed by NMR spectroscopy and mass spectrometry, and the data are as follows: 1 H NMR(400MHz,CDCl3)δ7.67(s,1H),7.63(d,J=8.0Hz,2H),7.55(d,J=8.4Hz,2H). 13 C NMR(150MHz,CDCl3)δ168.9,141.1,126.4(q,J=3.8Hz),126.2(d,J=33.0Hz),124.2(d,J=271.5Hz),119.5,24.5–24.0(m). 19 F NMR(565MHz,CDCl3)δ-62.1. 2 H NMR(61MHz,CHCl3)δ2.19(br,s).HRMSCalcd for C9H6D3F3NO[M+H] + :m / z 207.0820,Found:207.0822。

[0257] Example 56

[0258] Under the same conditions as in Example 51, 2,2-dichloro-N-(p-hydroxyphenyl)acetamide was used to replace 2,2-dichloro-N-phenylacetamide as the raw material. The finally obtained target product was a yellow oil with a yield of 74% and a deuteration rate of 93%.

[0259] The structural formula of the target product is as follows:

[0260] The yellow oil was analyzed by NMR spectroscopy and mass spectrometry, and the data are as follows: 1 H NMR(600MHz,DMSO-d6)δ9.64(s,1H),9.13(s,1H),7.34–7.31(m,2H),6.68–6.65(m,2H). 13 C NMR(150MHz,DMSO-d6)δ168.0,153.6,131.5,121.3,115.5,24.1–23.3(m). 21H NMR (61 MHz, CHCl3) δ 2.10 (br, s). HRMS Calcd for C8H7D3NO2 [M+H] + : m / z 155.0895, Found: 155.0890。

[0261] Example 57

[0262] Under the same conditions as in Example 51, 2,2-dichloro-N-(p-ethoxyphenyl)acetamide was used to replace 2,2-dichloro-N-phenylacetamide as the raw material. The finally obtained target product was a white solid with a yield of 77% and a deuteration rate of 91%.

[0263] The structural formula of the target product is as follows:

[0264] The nuclear magnetic spectroscopy and mass spectrometry analysis of the above white solid were carried out, and the data are as follows: 1 1H NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 7.38–7.34 (m, 2H), 6.84–6.80 (m, 2H), 4.02–3.96 (m, 2H), 1.40–1.36 (m, 3H). 13 13C NMR (150 MHz, CDCl3) δ 168.6, 155.9, 131.0, 122.1, 114.8, 63.8, 14.9, 24.0–23.7 (m). 2 1H NMR (61 MHz, CHCl3) δ 2.15 (br, s). HRMS Calcd for C 10 H 11 D3NO2 [M+H] + : m / z 183.1208, Found: 183.1207。

[0265] Example 58

[0266] Under the same conditions as in Example 51, benzyl (2,2-dichloroacetyl)-L-phenylpropionate was used to replace 2,2-dichloro-N-phenylacetamide as the raw material. The finally obtained target product was a white solid with a yield of 85% and a deuteration rate of 92%.

[0267] The structural formula of the target product is as follows:

[0268] The nuclear magnetic spectroscopy and mass spectrometry analysis of the above white solid were carried out, and the data are as follows: 11H NMR (600 MHz, CDCl3) δ 7.38–7.35 (m, 3H), 7.31–7.29 (m, 2H), 7.23–7.20 (m, 3H), 7.01–6.97 (m, 2H), 5.92 (d, J = 7.8 Hz, 1H), 5.18–5.11 (m, 2H), 4.95–4.91 (m, 1H), 3.15–3.08 (m, 2H). 13 13C NMR (150 MHz, CDCl3) δ 171.6, 169.8, 135.8, 135.2, 129.4, 128.78, 128.75, 128.71, 128.69, 127.2, 67.4, 53.2, 37.9, 23.1–22.4 (m). 2 1H NMR (61 MHz, CHCl3) δ 1.98 (br, s). HRMS Calcd for C 18 H 17 D3NO3 [M + H] + : m / z 301.1626, Found: 301.1629。

[0269] Example 59

[0270] Under the same conditions as in Example 51, the raw material 2,2-dichloro-N-(2-(5-methoxy-1H-indol-3-yl)ethyl)acetamide was used to replace 2,2-dichloro-N-phenylacetamide. The finally obtained target product was a yellow solid with a yield of 78% and a deuteration rate of 91%.

[0271] The structural formula of the target product is as follows:

[0272] The nuclear magnetic spectroscopy and mass spectrometry analysis of the above yellow solid gave the following data: 1 1H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 7.26–7.24 (m, 1H), 7.01 (dd, J = 14.8, 2.4 Hz, 2H), 6.86 (dd, J = 8.8, 2.4 Hz, 1H), 5.67 (s, 1H), 3.85 (s, 3H), 3.60–3.55 (m, 2H), 2.95–2.91 (m, 2H). 13 13C NMR (150 MHz, CDCl3) δ 170.4, 154.2, 131.7, 123.0, 112.7, 112.5, 112.2, 100.6, 56.1, 39.9, 25.4, 23.1–22.7 (m). 2 1H NMR (61 MHz, CHCl3) δ 1.23–1.21 (m). HRMS Calcd for C13 H 14 D3N2O2[M + H] + : m / z 236.1473, Found: 236.1477。

[0273] Example 60

[0274] Under the same conditions as in Example 51, the raw material (S)-2,2-dichloro-N-((3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide was used to replace 2,2-dichloro-N-phenylacetamide. The finally obtained target product was a yellow solid with a yield of 84% and a deuteration rate of 100%.

[0275] The structural formula of the target product is as follows:

[0276] The above yellow solid was analyzed by NMR spectroscopy and mass spectrometry, and the data are as follows: 1 H NMR(400MHz, CDCl3)δ7.42–7.37(m, 1H), 7.26–7.21(m, 1H), 7.08–7.04(m, 1H), 6.90(t, J = 9.0Hz, 1H), 4.81–4.75(m, 1H), 4.06–4.01(m, 1H), 3.86–3.83(m, 4H), 3.79–3.69(m, 2H), 3.66–3.59(m, 1H), 3.04–3.01(m, 4H). 13 C NMR(150MHz, CDCl3)δ167.4, 155.5(d, J = 246.0Hz), 154.3, 136.7(d, J = 8.8Hz), 132.9(d, J = 10.0Hz), 118.9(d, J = 4.0Hz), 114.1(d, J = 3.0Hz), 107.7(d, J = 26.2Hz), 71.6, 67.0, 51.0(d, J = 2.4Hz), 47.8, 42.6, 42.4–42.0(m). 19 F NMR(376MHz, CDCl3)δ - 120.1. 2 H NMR(61MHz, CHCl3)δ3.34(br, s). HRMS Calcd for C 16 H 18 D3FN3O4[M + H] + : m / z 341.1699, Found: 341.1698。

Claims

1. A photocatalytic preparation method of deuterated acetamide compounds, characterized in that: The same raw material dichloroacetamide is used to synthesize mono-deuterated acetamide compounds, bis-deuterated acetamide compounds, and tri-deuterated acetamide compounds; The specific synthesis process of the bis-deuterated acetamide compounds is as follows: Under a nitrogen environment at room temperature, the dichloroacetamide compound, photocatalyst, additive, solvent, and D2O are sequentially added to a reaction tube and subjected to a photocatalytic reaction. After the reaction is completed, the reaction solution is extracted with ethyl acetate and saturated sodium chloride. After combining the organic phases, the solvent is evaporated, and the residue is purified by silica gel chromatography to obtain the bis-deuterated acetamide compounds; The specific synthesis process of the mono-deuterated acetamide compounds is as follows: First, the dichloroacetamide compound, triethylamine (Et3N), acetonitrile (MeCN), and D2O are sequentially added to a reaction flask and reacted under a nitrogen environment at room temperature. After the reaction is completed, the reaction solution is extracted with ethyl acetate and saturated sodium chloride, and the organic phase is rotary evaporated to obtain deuterated dichloroacetamide compounds; Then, under a nitrogen environment at room temperature, the deuterated dichloroacetamide compounds, photocatalyst, additive, solvent, and H2O are sequentially added to a reaction tube and subjected to a photocatalytic reaction. After the reaction is completed, the reaction solution is extracted with ethyl acetate and saturated sodium chloride, the solvent is evaporated, and the residue is purified by silica gel chromatography to obtain the mono-deuterated acetamide compounds; The specific synthesis process of the tri-deuterated acetamide compounds is as follows: First, the dichloroacetamide compound, Et3N, MeCN, and D2O are added to a reaction flask and reacted under a nitrogen environment at room temperature. After the reaction is completed, the reaction solution is extracted with ethyl acetate and saturated sodium chloride, and the organic phase is rotary evaporated to obtain deuterated dichloroacetamide compounds; Then, under a nitrogen environment at room temperature, the deuterated dichloroacetamide compounds, photocatalyst, additive, solvent, and D2O are sequentially added to a reaction tube and subjected to a photocatalytic reaction. After the reaction is completed, the reaction solution is extracted with ethyl acetate and saturated sodium chloride, the solvent is evaporated, and the residue is purified by silica gel chromatography to obtain the tri-deuterated acetamide compounds; The structural formula of the dichloroacetamide compounds is shown in Formula A, the structural formula of the bis-deuterated acetamide compounds is shown in Formula B, the structural formula of the deuterated dichloroacetamide compounds is shown in Formula C, the structural formula of the mono-deuterated acetamide compounds is shown in Formula D, and the structural formula of the tri-deuterated acetamide compounds is shown in Formula E: In Formula A, Formula B, Formula C, Formula D and Formula E, R is phenyl, substituted phenyl, pyridine, benzyl, alkyl, tetrahydroisoquinoline, amino acid, dipeptide, drug or natural product, and the substituent on the benzene ring of the substituted phenyl is hydroxyl, C 1～5 alkyl, C 1～2 alkoxy, trifluoromethyl, ester group, phenyl, F, Cl or Br.

2. The photocatalytic preparation method of the deuterated acetamide compound according to claim 1, characterized in that The structural formula of the bis-deuterated acetamide compounds is: The structural formula of the mono-deuterated acetamide compounds is: The structural formula of the tri-deuterated acetamide compounds is:

3. The photocatalytic preparation method of the deuterated acetamide compound according to claim 1, characterized in that The deuterated acetamide compounds are mono-deuterated, bis-deuterated, and tri-deuterated derivatives of drugs or health products, and their structural formula is:

4. The photocatalytic preparation method of the deuterated acetamide compound according to claim 1, characterized in that The specific synthesis route of the bis-deuterated acetamide compounds is: The specific synthesis route of the mono-deuterated acetamide compounds is: The specific synthesis route of the tri-deuterated acetamide compounds is:

5. The photocatalytic preparation method of the deuterated acetamide compound according to claim 1, characterized in that: The photocatalytic reaction conditions for the synthesis process of the deuterated acetamide compounds are to react for 12 h under nitrogen conditions at room temperature, and the light source used for the photocatalytic reaction is an LED lamp with a wavelength of 405 nm and a power of 10 W.

6. The photocatalytic preparation method of the deuterated acetamide compound according to claim 1, wherein: The photocatalyst is one or more of rhodamine B, rhodamine 6G, eosin Y, rose bengal, fluorescein, methylene blue, sodium fluorescein, and 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile, and the structural formula of 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile is as follows:

7. The photocatalytic preparation method of the deuterated acetamide compound according to claim 1, wherein: The additive is one or more of triethylamine, N,N-diisopropylethylamine, tetramethylethylenediamine, triethylenediamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, and lithium hydroxide.

8. The photocatalytic preparation method of the deuterated acetamide compound according to claim 1, characterized in that: The solvent is one or more of acetonitrile, tetrahydrofuran, N,N-dimethylacetamide, methanol, N-methylpyrrolidone, N,N-dimethylformamide, 2-methyltetrahydrofuran, dimethyl carbonate, dichloromethane, toluene, dimethyl sulfoxide, 1,4-dioxane, and polyethylene glycol.

9. The photocatalytic preparation method of the deuterated acetamide compound according to claim 1, wherein: In the synthesis process of the bis-deuterated acetamide compound, the molar ratio of the dichloroacetamide compound, the photocatalyst to the additive is 1:0.01-0.1:1-5; In the synthesis process of the mono-deuterated acetamide compound, the molar ratio of the deuterated dichloroacetamide compound, the photocatalyst to the additive is 1:0.01-0.1:1-5; In the synthesis process of the tri-deuterated acetamide compound, the molar ratio of the deuterated dichloroacetamide compound, the photocatalyst to the additive is 1:0.01-0.1:1-5.

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