Photocatalytic preparation method of deuterated lidocaine derivative

Abstract

The invention discloses a photocatalytic preparation method of a deuterated lidocaine derivative, which specifically comprises the following steps: sequentially adding a dichloroacetamide compound, a photocatalyst, triethylamine, a solvent and D2O into a reaction tube in a room-temperature air environment, carrying out an illumination reaction at 40-50 DEG C, extracting a reaction solution by using ethyl acetate and saturated sodium chloride after the reaction is finished, filtering, washing, and drying to obtain the deuterated lidocaine derivative. And after combining the organic phases, evaporating to remove the solvent, and purifying residues by silica gel chromatography to obtain the target product deuterated lidocaine derivative. According to the preparation method disclosed by the invention, cheap deuterated water is used as a deuterium source, so that the use of expensive deuterated formaldehyde is avoided. The preparation method has the advantages of simple and safe operation, mild reaction conditions, no transition metal participation, cheap and easily available deuterium source and the like.

Description

Technical Field

[0001] The present invention belongs to the technical field of the synthesis of deuterated lidocaine derivatives, and particularly relates to a photocatalytic preparation method of deuterated lidocaine derivatives. Background Art

[0002] The deuteration strategy is a drug structure modification strategy that replaces hydrogen atoms in the drug molecular structure with deuterium atoms, which can improve the pharmacokinetic properties, in vivo safety, and stereostability of compounds (Eur. J. Med. Chem., 2025, 287, 117371). With the listing of deuterated drugs such as deutetrabenazine, deucravacitinib, donafenib, and deuremidevir, the deuteration strategy has become one of the most efficient strategies in drug research and development (Nat. Rev. Drug Discov., 2023, 22, 562 - 584; ChemMedChem 2024, e202400836).

[0003] Lidocaine is widely used in local infiltration, nerve block, intraspinal anesthesia, and anti - arrhythmia due to its rapid onset (1 - 3 min), low toxicity at therapeutic doses, low price, and can be used alone or in combination with other drugs. It can also be safely used in special populations such as pregnant women and children. Compared with other local anesthetics such as ropivacaine, levobupivacaine, liposomal bupivacaine, and articaine, it still has advantages in pharmacokinetics, price, application scenarios, etc. and is irreplaceable. Using the deuteration strategy to modify the structure of this drug and synthesize deuterated lidocaine derivatives is expected to improve pharmacokinetic properties, reduce the dosage, and break through the original patented technology to obtain new drug molecules. Currently, there is little research on the synthesis of deuterated lidocaine. In 2024, the Gaunt research group reported a method for synthesizing deuterated lidocaine using expensive and hard - to - obtain deuterated formaldehyde (1 g > 10,000 yuan) (J. Am. Chem. Soc. 2024, 146, 24699–24707), which greatly limits the research and development and clinical application of this type of drug. Therefore, developing a synthesis method for deuterated lidocaine derivatives with high efficiency and easily available deuterium sources 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 of deuterated lidocaine derivatives that is simple and safe to operate, has mild reaction conditions, and uses heavy water as the deuterium source, so as to solve the problem of the expensive deuterium source used in the current synthesis method of deuterated lidocaine derivatives.

[0005] The present invention adopts the following technical solution to solve the above technical problems: A photocatalytic preparation method of a deuterated lidocaine derivative, characterized in that the specific preparation process is as follows: In a room-temperature air environment, a dichloroacetamide compound, a photocatalyst, triethylamine, a solvent, and D2O are sequentially added to a reaction tube, and a photoirradiation reaction is carried out at 40-50 °C. 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 target product, the deuterated lidocaine derivative;

[0006] The structural formula of the dichloroacetamide compound is shown in Formula A, and the structural formula of the deuterated lidocaine derivative is shown in Formula B:

[0007]

[0008] Wherein R is a phenyl group or a substituted phenyl group, and the substituents on the benzene ring of the substituted phenyl group are one or more of C 1～5 alkyl, hydroxyl group, C 1～5 alkoxy group, trifluoromethyl group, ester group, F, Cl, and Br;

[0009] 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. The structural formula of 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile is:

[0010]

[0011] Further defined, the structural formula of the deuterated lidocaine derivative is:

[0012]

[0013] Further defined, the specific synthesis route of the deuterated lidocaine derivative is:

[0014]

[0015] Further defined, the photocatalytic reaction conditions in the synthesis process of the deuterated lidocaine derivative are a reaction at 45 °C for 12 h under air conditions, and the light source used in the photoirradiation reaction is an LED lamp with a wavelength of 475 nm and a power of 10 W.

[0016] Further defined, the solvent is one or more of acetonitrile, dichloromethane, methanol, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl carbonate, toluene, N,N-dimethylacetamide, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and polyethylene glycol, preferably acetonitrile.

[0017] Further defined, the molar ratio of the dichloroacetamide compound, the photocatalyst and triethylamine is 1:0.03 - 0.1:3 - 10, preferably 1:0.08:8.

[0018] Compared with the prior art, the present invention has the following advantages and beneficial effects: The present invention provides a preparation method of a deuterated lidocaine derivative. Compared with the prior art, the preparation method of the present invention uses inexpensive deuterated water as the deuterium source, avoiding the use of expensive deuterated formaldehyde. The preparation method of the present invention has the advantages of simple and safe operation, mild reaction conditions, no participation of transition metals, and inexpensive and easily available deuterium source. Detailed implementation manners

[0019] The above content of the present invention will be further described in detail through the following examples. However, it should not be understood that the scope of the above subject matter of the present invention is limited to the following examples. All technologies implemented based on the above content of the present invention belong to the scope of the present invention.

[0020] Example 1

[0021] 2,2 - Dichloro - N - (o - xylyl) acetamide (0.2 mmol), 4CzIPN (8 mol%), Et3N (8.0 equivalents), D2O (0.4 mL) and anhydrous MeCN (2.5 mL) were successively added to a 10 mL reaction tube with a magnetic stir bar, and the reaction was carried out at 45 °C under irradiation with a 10 W 475 nm LED lamp for 12 hours. After the reaction was completed, the reaction mixture was quenched with saturated NaCl aqueous 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 oil with a yield of 48% and a deuteration rate of 93%.

[0022] The structural formula of the target product is as follows:

[0023] The above yellow oil was analyzed by nuclear magnetic spectroscopy and mass spectrometry, and the data are as follows: 1 H NMR(400MHz,CDCl3)δ8.94(s,1H),7.07(s,3H),2.69(q,J = 7.2Hz,4H),2.22(s,6H),1.13(t,J = 7.2Hz,6H). 13 CNMR(150MHz,CDCl3)δ170.1,135.1,134.0,128.2,127.0,57.2–56.5(m),48.9,18.6,12.6. 2 HNMR(61MHz,CHCl3)δ3.26(br,s).HRMS Calcd for C14 H 21 D2N2O[M + H] + : m / z 237.1931, Found: 237.1936。

[0024] Example 2

[0025] Under the same conditions as in Example 1, the raw material 2,2-dichloro-N-phenylacetamide was used to replace 2,2-dichloro-N-(o-xylenyl)acetamide. The finally obtained target product was a yellow oil, with a yield of 64% and a deuteration rate of 92%.

[0026] The structural formula of the target product is as follows:

[0027] 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)δ9.41(s, 1H), 7.59–7.56(m, 2H), 7.36–7.31(m, 2H), 7.12–7.08(m, 1H), 2.68–2.62(m, 4H), 1.10(t, J = 7.2Hz, 6H). 13 C NMR(150MHz, CDCl3)δ170.3, 137.9, 129.2, 124.2, 119.5, 58.3–57.6(m), 49.0, 12.6. 2 H NMR(61MHz, CHCl3)δ3.16(br, s). HRMS Calcd for C 12 H 17 D2N2O[M + H] + : m / z 209.1618, Found: 209.1617。

[0028] Example 3

[0029] 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-(o-xylenyl)acetamide. The finally obtained target product was a yellow oil, with a yield of 39% and a deuteration rate of 92%.

[0030] The structural formula of the target product is as follows:

[0031] The nuclear magnetic resonance spectrum and mass spectrum of the above light yellow oil were analyzed, and the data are as follows: 11H NMR (600 MHz, CDCl3) δ 9.35 (s, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 7.8 Hz, 2H), 2.67–2.63 (m, 4H), 2.31 (s, 3H), 1.09 (t, J = 7.2 Hz, 6H). 13 13C NMR (150 MHz, CDCl3) δ 170.0, 135.3, 133.8, 129.6, 119.5, 58.0–57.5 (m), 48.9, 21.0, 12.5. 2 1H NMR (61 MHz, CHCl3) δ 3.17 (br, s). HRMS Calcd for C 13 H 19 D2N2O [M + H] + : m / z 223.1774, Found: 223.1776。

[0032] Example 4

[0033] Under the same conditions as in Example 1, 2,2-dichloro-N-(p-ethylphenyl)acetamide was used to replace 2,2-dichloro-N-(o-xylenyl)acetamide as the raw material. The finally obtained target product was a yellow oil, with a yield of 49% and a deuteration rate of 94%.

[0034] The structural formula of the target product is as follows:

[0035] The above yellow oil was analyzed by nuclear magnetic spectroscopy and mass spectrometry, and the data are as follows: 1 1H NMR (400 MHz, CDCl3) δ 9.37 (s, 1H), 7.50–7.47 (m, 2H), 7.17–7.15 (m, 2H), 2.68–2.59 (m, 6H), 1.21 (t, J = 7.6 Hz, 3H), 1.09 (t, J = 7.2 Hz, 6H). 13 13C NMR (150 MHz, CDCl3) δ 170.2, 140.3, 135.5, 128.5, 119.6, 57.6–57.4 (m), 49.0, 28.5, 15.9, 12.6. 2 1H NMR (61 MHz, CHCl3) δ 3.18 (br, s). HRMS Calcd for C 14 H 21 D2N2O [M + H] + : m / z 237.1931, Found: 237.1933。

[0036] Example 5

[0037] Under the same conditions as in Example 1, the raw material 2,2-dichloro-N-(p-ethoxyphenyl)acetamide was used to replace 2,2-dichloro-N-(o-xylenyl)acetamide. The finally obtained target product was a yellow oil, with a yield of 32% and a deuteration rate of 93%.

[0038] The structural formula of the target product is as follows:

[0039] The nuclear magnetic spectroscopy and mass spectrometry analysis of the above yellow oil were carried out, and the data are as follows: 1 H NMR(400MHz,CDCl3)δ9.31(s,1H),7.49–7.44(m,2H),6.88–6.83(m,2H),4.04–3.98(m,2H),2.68–2.63(m,4H),1.41–1.37(m,3H),1.09(t,J=7.2Hz,6H). 13 C NMR(150MHz,CDCl3)δ155.7,131.0,126.1121.1,115.0,63.9,57.7–57.2(m),48.9,15.0,12.5. 2 H NMR(61MHz,CHCl3)δ3.14(br,s).HRMS Calcd for C 14 H 21 D2N2O2[M+H] + :m / z 253.1880,Found:253.1881。

[0040] Example 6

[0041] Under the same conditions as in Example 1, the raw material 2,2-dichloro-N-(p-ethoxyphenyl)acetamide was used to replace 2,2-dichloro-N-(o-xylenyl)acetamide. The finally obtained target product was a yellow oil, with a yield of 63% and a deuteration rate of 92%.

[0042] The structural formula of the target product is as follows:

[0043] The nuclear magnetic spectroscopy and mass spectrometry analysis of the above yellow oil were carried out, and the data are as follows: 1 H NMR(600MHz,CDCl3)δ9.43(s,1H),7.49(d,J=8.4Hz,2H),7.14(d,J=8.4Hz,2H),2.73-2.68(m,4H),2.58–2.55(m,2H),1.60–1.54(m,2H),1.37–1.31(m,2H),1.12(t,J=7.2Hz,6H),0.93–0.90(m,3H).13 CNMR (150 MHz, CDCl3) δ 169.9, 139.0, 135.5, 129.0, 119.5, 57.5–57.1 (m), 49.0, 48.9, 35.2, 33.8, 22.4, 14.1. 2 H NMR (61 MHz, CHCl3) δ 3.24 (br, s). HRMS Calcd for C 16 H 25 D2N2O [M + H] + : m / z 265.2244, Found: 265.2248。

[0044] Example 7

[0045] Under the same conditions as in Example 1, 2,2-dichloro-N-(p-tert-butylphenyl)acetamide was used to replace 2,2-dichloro-N-(o-xylene)acetamide as the raw material. The finally obtained target product was a yellow oil, with a yield of 44% and a deuteration rate of 92%.

[0046] The structural formula of the target product is as follows:

[0047] The above yellow solid was analyzed by NMR spectroscopy and mass spectrometry, and the data are as follows: 1 H NMR (400 MHz, CDCl3) δ 9.35 (s, 1H), 7.51–7.48 (m, 2H), 7.37–7.33 (m, 2H), 2.64 (q, J = 7.2 Hz, 4H), 1.31 (s, 9H), 1.08 (t, J = 7.2 Hz, 6H). 13 C NMR (150 MHz, CDCl3) δ 170.2, 147.2, 135.2, 125.9, 119.3, 58.0–57.1 (m), 49.0, 34.5, 31.5, 12.6. 2 H NMR (61 MHz, CHCl3) δ 3.13 (br, s). HRMS Calcd for C 16 H 25 D2N2O [M + H] + : m / z 265.2244, Found: 265.2245。

[0048] Example 8

[0049] Under the same conditions as in Example 1, 2,2-dichloro-N-(m-methylphenyl)acetamide was used to replace 2,2-dichloro-N-(o-xylene)acetamide as the raw material. The finally obtained target product was a yellow oil, with a yield of 40% and a deuteration rate of 94%.

[0050] The structural formula of the target product is as follows:

[0051] The above yellow oil was analyzed by NMR spectroscopy and mass spectrometry, and the data are as follows: 1 H NMR(400MHz,CDCl3)δ9.35(s,1H),7.41(s,1H),7.37(d,J=8.4Hz,1H),7.23–7.19(m,1H),6.92(d,J=7.6Hz,1H),2.67–2.61(m,4H),2.35(s,3H),1.09(t,J=7.2Hz,6H). 13 C NMR(150MHz,CDCl3)δ170.2,139.1,137.8,129.0,125.0,120.0,116.5,58.1–57.5(m),49.0,21.6,12.6. 2 H NMR(61MHz,CHCl3)δ3.17(br,s).HRMS Calcd for C 13 H 19 D2N2O[M+H] + :m / z 223.1774,Found:223.1772。

[0052] Example 9

[0053] Under the same conditions as in Example 1, 2,2-dichloro-N-(o-ethylphenyl)acetamide was used to replace 2,2-dichloro-N-(o-dimethylphenyl)acetamide. The finally obtained target product was a yellow oil with a yield of 37% and a deuteration rate of 95%.

[0054] The structural formula of the target product is as follows:

[0055] The above yellow oil was analyzed by NMR spectroscopy and mass spectrometry, and the data are as follows: 1 H NMR(600MHz,CDCl3)δ9.58(s,1H),8.15(d,J=8.4Hz,1H),7.24–7.21(m,1H),7.20–7.18(m,1H),7.08(td,J=7.8,1.2Hz,1H),2.67(q,J=7.2Hz,4H),2.65–2.60(m,2H),1.27–1.24(m,3H),1.11(t,J=7.2Hz,6H). 1313C NMR (150 MHz, CDCl3) δ 170.1, 135.5, 133.1, 128.7, 127.0, 124.6, 121.4, 58.4–57.7 (m), 48.8, 24.7, 14.3, 12.7. 2 1H NMR (61 MHz, CHCl3) δ 3.21 (br, s). HRMS Calcd for C 14 H 21 D2N2O [M + H] + : m / z 237.1931, Found: 237.1931。

[0056] Example 10

[0057] Under the same conditions as in Example 1, the raw material 2,2-dichloro-N-(p-hydroxyphenyl)acetamide was used to replace 2,2-dichloro-N-(o-dimethylphenyl)acetamide. The finally obtained target product was a yellow oil, with a yield of 41% and a deuteration rate of 93%.

[0058] The structural formula of the target product is as follows:

[0059] The nuclear magnetic spectroscopy and mass spectrometry analysis of the above yellow oil are as follows: 1 1H NMR (400 MHz, CDCl3) δ 9.33 (s, 1H), 7.39–7.34 (m, 2H), 6.83–6.79 (m, 2H), 2.64 (q, J = 7.2 Hz, 4H), 1.08 (t, J = 7.2 Hz, 6H). 13 13C NMR (150 MHz, CDCl3) δ 170.5, 153.5, 130.1, 121.8, 115.9, 57.7–57.1 (m), 48.9, 12.5. 2 1H NMR (61 MHz, CHCl3) δ 3.12 (br, s). HRMS Calcd for C 12 H 17 D2N2O2 [M + H] + : m / z 225.1567, Found: 225.1566。

[0060] Example 11

[0061] Under the same conditions as in Example 1, the raw material 2,2-dichloro-N-(m-dimethylphenyl)acetamide was used to replace 2,2-dichloro-N-(o-dimethylphenyl)acetamide. The finally obtained target product was a yellow oil, with a yield of 45% and a deuteration rate of 93%.

[0062] The structural formula of the target product is as follows:

[0063] The above yellow oil was analyzed by nuclear magnetic spectroscopy and mass spectrometry, and the data are as follows: 1 H NMR(400MHz,CDCl3)δ9.31(s,1H),7.21(s,2H),6.75(s,1H),2.67–2.61(m,4H),2.31(s,6H),1.10–1.06(m,6H). 13 C NMR(150MHz,CDCl3)δ170.2,138.9,137.7,126.0,117.2,58.1–57.5(m),49.0,21.5,12.6. 2 H NMR(61MHz,CHCl3)δ3.11(br,s).HRMS Calcd for C 14 H 21 D2N2O[M+H] + :m / z237.1931,Found:237.1930。

[0064] Example 12

[0065] Under the same conditions as in Example 1, 2,2-dichloro-N-(p-trifluoromethylphenyl)acetamide was used to replace 2,2-dichloro-N-(o-dimethylphenyl)acetamide. The finally obtained target product was a yellow oil, with a yield of 41% and a deuteration rate of 92%.

[0066] The structural formula of the target product is as follows:

[0067] The above yellow solid was analyzed by nuclear magnetic spectroscopy and mass spectrometry, and the data are as follows: 1 H NMR(400MHz,CDCl3)δ9.61(s,1H),7.70(d,J=8.4Hz,2H),7.58(d,J=8.4Hz,2H),2.69–2.63(m,4H),1.10(t,J=7.2Hz,6H). 13 C NMR(150MHz,CDCl3)δ170.7,140.8,126.4(q,J=4.1Hz),126.0(q,J=32.5Hz),124.3(d,J=271.5Hz),119.0,58.2–57.2(m),49.0,12.6. 19 F NMR(376MHz,CDCl3)δ-62.1. 2 H NMR(61MHz,CHCl3)δ3.21(br,s).HRMS Calcd for C 13 H16 D2F3N2O[M+H] + : m / z 277.1492, Found: 277.1499。

[0068] Example 13

[0069] Under the same conditions as in Example 1, 2,2-dichloro-N-(p-fluorophenyl)acetamide was used to replace 2,2-dichloro-N-(o-dimethylphenyl)acetamide as the raw material. The finally obtained target product was a yellow oil, with a yield of 58% and a deuteration rate of 96%.

[0070] The structural formula of the target product is as follows:

[0071] The nuclear magnetic resonance spectrum and mass spectrum of the above yellow oil were analyzed, and the data are as follows: 1 H NMR (400 MHz, CDCl3) δ 9.46 (s, 1H), 7.56–7.51 (m, 2H), 7.05–6.98 (m, 2H), 2.68 (q, J = 7.2 Hz, 4H), 1.10 (t, J = 7.2 Hz, 6H). 13 C NMR (150 MHz, CDCl3) δ 170.2, 159.4 (d, J = 243.0 Hz), 134.0 (d, J = 3.0 Hz), 121.1 (d, J = 7.5 Hz), 115.8 (d, J = 22.2 Hz), 58.1–57.2 (m), 49.0, 12.6. 19 F NMR (565 MHz, CDCl3) δ -118.4. 2 H NMR (61 MHz, CHCl3) δ 3.19 (br, s). HRMS Calcd for C 12 H 16 D2FN2O[M+H] + : m / z 227.1524, Found: 227.1524。

[0072] Example 14

[0073] Under the same conditions as in Example 1, 2,2-dichloro-N-(p-chlorophenyl)acetamide was used to replace 2,2-dichloro-N-(o-dimethylphenyl)acetamide as the raw material. The finally obtained target product was a yellow oil, with a yield of 33% and a deuteration rate of 92%.

[0074] The structural formula of the target product is as follows:

[0075] The nuclear magnetic resonance spectrum and mass spectrum of the above yellow oil were analyzed, and the data are as follows: 11H NMR (400 MHz, CDCl3) δ 9.43 (s, 1H), 7.55–7.51 (m, 2H), 7.31–7.26 (m, 2H), 2.67–2.61 (m, 4H), 1.08 (t, J = 7.2 Hz, 6H). 13 13C NMR (150 MHz, CDCl3) δ 170.4, 136.5, 129.2, 129.1, 120.6, 58.0–57.3 (m), 49.0, 12.6. 2 1H NMR (61 MHz, CHCl3) δ 3.18 (br, s). HRMS Calcd for C 12 H 16 D2ClN2O [M + H] + : m / z 243.1228, Found: 243.1227。

[0076] Example 15

[0077] Under the same conditions as in Example 1, the raw material 2,2-dichloro-N-(m-fluorophenyl)acetamide was used to replace 2,2-dichloro-N-(o-dimethylphenyl)acetamide. The finally obtained target product was a yellow oil, with a yield of 38% and a deuteration rate of 94%.

[0078] The structural formula of the target product is as follows:

[0079] 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 (600 MHz, CDCl3) δ 9.59 (s, 1H), 7.54 (dt, J = 10.8, 2.4 Hz, 1H), 7.29–7.24 (m, 1H), 7.22 (d, J = 7.8 Hz, 1H), 6.81–6.78 (m, 1H), 2.69 (q, J = 7.2 Hz, 4H), 1.11 (t, J = 7.2 Hz, 6H). 13 13C NMR (150 MHz, CDCl3) δ 170.4, 163.3 (d, J = 244.5 Hz), 139.4 (d, J = 11.0 Hz), 130.2 (d, J = 9.9 Hz), 114.7 (d, J = 2.5 Hz), 110.9 (d, J = 21.8 Hz), 106.9 (d, J = 26.4 Hz), 58.0–57.3 (m), 49.0, 12.6. 19 19F NMR (565 MHz, CDCl3) δ -111.6. 2 1H NMR (61 MHz, CHCl3) δ 3.19 (br, s). HRMS Calcd for C12 H 16 D2FN2O[M+H] + : m / z 227.1524, Found: 227.1521。

[0080] Example 16

[0081] Under the same conditions as in Example 1, the raw material 2,2-dichloro-N-(m-chlorophenyl)acetamide was used to replace 2,2-dichloro-N-(o-dimethylphenyl)acetamide. The finally obtained target product was a yellow oil, with a yield of 45% and a deuteration rate of 92%.

[0082] The structural formula of the target product is as follows:

[0083] 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)δ9.57(s, 1H), 7.67(t, J = 2.0Hz, 1H), 7.47–7.44(m, 1H), 7.26–7.22(m, 1H), 7.09–7.06(m, 1H), 2.69(q, J = 7.2Hz, 4H), 1.11(t, J = 7.2Hz, 6H). 13 C NMR(150MHz, CDCl3)δ167.0, 139.0, 134.8, 130.2, 124.3, 119.5, 117.5, 57.5–57.1(m), 48.9, 12.4. 2 H NMR(61MHz, CHCl3)δ3.18(br, s). HRMS Calcd for C 12 H 16 D2ClN2O[M+H] + : m / z 243.1228, Found: 243.1227。

[0084] Example 17

[0085] Under the same conditions as in Example 1, the raw material 2,2-dichloro-N-(m-bromophenyl)acetamide was used to replace 2,2-dichloro-N-(o-dimethylphenyl)acetamide. The finally obtained target product was a yellow oil, with a yield of 46% and a deuteration rate of 95%.

[0086] The structural formula of the target product is as follows:

[0087] The nuclear magnetic resonance spectrum and mass spectrum of the above yellow oil were analyzed, and the data are as follows: 11H NMR (400 MHz, CDCl3) δ 9.45 (s, 1H), 7.78 (t, J = 2.0 Hz, 1H), 7.54–7.51 (m, 1H), 7.24–7.16 (m, 2H), 2.64 (q, J = 7.2 Hz, 4H), 1.08 (t, J = 7.2 Hz, 6H). 13 13C NMR (150 MHz, CDCl3) δ 170.4, 139.1, 130.5, 127.1, 122.8, 122.3, 117.9, 57.8–57.3 (m), 49.0, 12.6. 2 1H NMR (61 MHz, CHCl3) δ 3.18 (br, s). HRMS Calcd for C 12 H 16 D2BrN2O [M + H] + : m / z 287.0723, Found: 287.0723。

[0088] Example 18

[0089] Under the same conditions as in Example 1, the raw material 2,2-dichloro-N-(m-bromophenyl)acetamide was used to replace 2,2-dichloro-N-(o-dimethylphenyl)acetamide, and the finally obtained target product was a yellow oil with a yield of 48% and a deuteration rate of 96%.

[0090] The structural formula of the target product is as follows:

[0091] The nuclear magnetic spectroscopy and mass spectrometry analysis of the above yellow oil are as follows: 1 1H NMR (400 MHz, CDCl3) δ 9.64 (s, 1H), 8.01 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.8 Hz, 2H), 3.90 (s, 3H), 2.66 (q, J = 7.2 Hz, 4H), 1.10 (t, J = 7.2 Hz, 6H). 13 13C NMR (150 MHz, CDCl3) δ 170.7, 166.8, 141.9, 131.0, 125.6, 118.6, 58.3–57.7 (m), 52.1, 49.0, 12.5. 2 1H NMR (61 MHz, CHCl3) δ 3.20 (br, s). HRMS Calcd for C 14 H 19 D2N2O3 [M + H] + : m / z 267.1673, Found: 267.1673。

[0092] Example 19

[0093] Under the same conditions as in Example 1, the raw material 2,2-dichloro-N-(3-chloro-4-fluorophenyl)acetamide was used to replace 2,2-dichloro-N-(o-dimethylphenyl)acetamide. The finally obtained target product was a yellow oil, with a yield of 65% and a deuteration rate of 94%.

[0094] The structural formula of the target product is as follows:

[0095] The above yellow oil was analyzed by nuclear magnetic spectroscopy and mass spectrometry, and the data are as follows: 1 H NMR(400MHz,CDCl3)δ9.43(s,1H),7.73(dd,J=6.4,2.8Hz,1H),7.44–7.39(m,1H),7.11–7.06(m,1H),2.67–2.61(m,4H),1.08(t,J=7.2Hz,6H). 13 C NMR(150MHz,CDCl3)δ170.4,154.7(d,J=246.2Hz),134.6(d,J=3.4Hz),121.5,121.3(d,J=18.6Hz),119.0(d,J=7.4Hz),116.8(d,J=22.0Hz),58.1–57.2(m),49.0,12.6. 19 F NMR(376MHz,CDCl3)δ-121.0. 2 H NMR(61MHz,CHCl3)δ3.19(br,s).HRMS Calcd for C 12 H 15 D2ClFN2O[M+H] + :m / z 261.1134,Found:261.1135。

[0096] Example 20

[0097] Under the same conditions as in Example 1, the raw material 2,2-dichloro-N-(3-chloro-4-fluorophenyl)acetamide was used to replace 2,2-dichloro-N-(o-dimethylphenyl)acetamide. The finally obtained target product was a yellow oil, with a yield of 53% and a deuteration rate of 92%.

[0098] The structural formula of the target product is as follows:

[0099] The above yellow oil was analyzed by nuclear magnetic spectroscopy and mass spectrometry, and the data are as follows: 11H NMR (400 MHz, CDCl3) δ 9.33 (s, 1H), 7.42–7.40 (m, 1H), 7.35–7.30 (m, 1H), 6.97–6.92 (m, 1H), 2.64 (q, J = 7.2 Hz, 4H), 2.26 (d, J = 2.0 Hz, 3H), 1.09 (t, J = 7.2 Hz, 6H). 13 13C NMR (150 MHz, CDCl3) δ 170.1, 158.0 (d, J = 241.1 Hz), 133.6 (d, J = 2.9 Hz), 125.5 (d, J = 18.6 Hz), 122.5 (d, J = 4.4 Hz), 118.4 (d, J = 7.7 Hz), 115.3 (d, J = 23.1 Hz), 58.1–57.3 (m), 49.0, 14.8 (d, J = 3.3 Hz), 12.6. 19 19F NMR (565 MHz, CDCl3) δ -122.7. 2 1H NMR (61 MHz, CHCl3) δ 3.16 (br, s). HRMS Calcd for C 13 1H 18 D2FN2O [M+H] + : m / z 241.1680, Found: 241.1683。

[0100] The above embodiments describe the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited by the above embodiments. What is described in the above embodiments and the specification only illustrates the principles of the present invention. Without departing from the scope of the principles of the present invention, the present invention will have various changes and improvements, and these changes and improvements all fall within the scope of protection of the present invention.

Claims

1. A photocatalytic preparation method of a deuterated lidocaine derivative, characterized in that The specific preparation process is as follows: Under the ambient air condition at room temperature, a dichloroacetamide compound, a photocatalyst, triethylamine, a solvent and D2O are successively added into a reaction tube, and a photoirradiation reaction is carried out at 40-50 °C. 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 target product deuterated lidocaine derivative; The structural formula of the dichloroacetamide compound is shown as Formula A, and the structural formula of the deuterated lidocaine derivative is shown as Formula B: wherein R is phenyl or substituted phenyl, and the substituents on the benzene ring of the substituted phenyl are one or more of C 1～5 alkyl, hydroxyl, C 1～5 alkoxy, trifluoromethyl, ester group, F, Cl and Br; 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:

2. The photocatalytic preparation method of a deuterated lidocaine derivative according to claim 1, characterized in that The structural formula of the deuterated lidocaine derivative is:

3. The photocatalytic preparation method of a deuterated lidocaine derivative according to claim 1, characterized in that The specific synthesis route of the deuterated lidocaine derivative is:

4. The photocatalytic preparation method of a deuterated lidocaine derivative according to claim 1, characterized in that: The photocatalytic reaction conditions in the synthesis process of the deuterated lidocaine derivative are: reacting at 45 °C for 12 h under air condition, and the light source used for the photoirradiation reaction is an LED lamp with a wavelength of 475 nm and a power of 10 W.

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

6. The photocatalytic preparation method of a deuterated lidocaine derivative according to claim 1, wherein: The molar ratio of the dichloroacetamide compound, the photocatalyst and triethylamine in the feed is 1:0.03-0.1:3-10.

7. The photocatalytic preparation method of a deuterated lidocaine derivative according to claim 1, characterized in that: The molar ratio of the dichloroacetamide compound, the photocatalyst and triethylamine in the feed is 1:0.08:8.

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