A method for synthesizing α-substituted deuterated amino acid ester

Abstract

The invention discloses a method for synthesizing an α-substituted deuterated amino acid ester. The method uses easily available amines, aldehyde (keto) acid esters and deuterated Hans esters as starting materials, and uses a cheap calcium catalyst to synthesize the deuterated amino acid through a reductive amination reaction. The method has mild conditions, simple operation, high efficiency and generality, and solves the problems of narrow applicable substrate range, complicated reaction steps and harsh reaction conditions in the prior art.

Description

Technical Field:

[0001] The present invention relates to a method for synthesizing α-substituted deuterated amino acid esters. Background Art:

[0002] Currently, with the rapid development of the field of medicinal chemistry, amino acids, in addition to being the basic structural units of proteins and polypeptides, are also often applied in fields such as medicine, food, cosmetics, and materials. Amino acids have extensive application values, but the types of amino acids encoded by genes are limited. Therefore, it has become an urgent need to develop an efficient method for amino acid modification. Deuterated compounds refer to those in which one or more hydrogen atoms at specific sites of certain compounds are replaced by deuterium atoms. It has been found that deuteration may change drug metabolism, reduce the drug metabolism rate, help extend the half-life, reduce toxicity, change molecular chirality or increase molecular stability, etc., thereby reducing the dosing frequency and dose, while improving biological activity, clinical efficacy, safety, and tolerance; deuteration has been applied to drug metabolism research and new drug development, etc. In 2017, the FDA approved the first deuterated drug - Austedo, for the treatment of Huntington's disease. α-deuterated amino acids are a special type of isotope-labeled compound, and deuterated amino acids have extensive applications in explaining aspects such as the biosynthetic pathways of peptides / proteins, the mechanisms and structures of enzymes, etc.

[0003] Based on the important role of the above-mentioned α-deuterated amino acids, the academic community has been committed to developing efficient synthesis methods. Currently, the methods for synthesizing deuterated amino acids mainly include the heavy water exchange method, chemical synthesis method, and biosynthesis method. The heavy water exchange method is often accompanied by disadvantages such as long reaction time, high energy consumption, and low selectivity; although the biosynthesis method can synthesize some compounds with complex structures and certain biological activities, it is restricted by the types and activities of enzymes, and the number of deuterium-labeled amino acids that can be synthesized is small. For the deuterated amino acids synthesized by the chemical synthesis method, their configurations are clear and the deuteration positions can be controlled, the reaction is simple, and the deuterium atom utilization rate is high. It is currently the most important way to obtain deuterated amino acid derivatives. In the chemical synthesis method, it can be further divided into photocatalytic synthesis method and metal-catalyzed synthesis method. For example, Liu used Hantzsch ester as a radical donor to carry out a radical addition reaction under the action of light to synthesize α-deuterated amino acids, but there are disadvantages such as a narrow substrate scope. The synthesis of α-deuterated amino acids has been most deeply studied with metal catalysis. Metal catalysts such as platinum, ruthenium, copper, iridium, and iron have all been studied and applied to the synthesis of α-deuterated amino acids. Dai adopted a Rh / Cu co-catalytic system to carry out an asymmetric reduction reaction of aromatic α-dehydro amino acid esters to prepare chiral deuterated α-amino esters. This reaction requires the protection treatment of amino acids, and the reaction steps are cumbersome. However, most of these methods reported so far have disadvantages such as a narrow substrate scope, cumbersome reaction steps, and harsh reaction conditions. Summary of the Invention:

[0004] The object of the present invention is to provide a method for synthesizing α-substituted deuterated amino acid esters, which uses readily available amines, aldehyde (ketone) acid esters and deuterated Hantzsch esters as starting materials, and synthesizes deuterated amino acids through reductive amination reaction with the aid of inexpensive calcium catalysts. The method has mild conditions, simple operation, high efficiency and generality, and solves the problems of narrow substrate scope, cumbersome reaction steps and harsh reaction conditions in the prior art.

[0005] The present invention is realized through the following technical solutions:

[0006] A method for synthesizing α-substituted deuterated amino acid ester compounds, the method comprising the following steps: using amines, aldehyde (ketone) acid esters and deuterated Hantzsch esters as starting materials, and synthesizing through reductive amination reaction with Ca(NTf 2 ) 2 as the catalyst; the reaction equation is as follows:

[0007]

[0008] In the formula, R 1 is selected from any one of hydrogen, C1-C2 alkyl, and halogen; R 2 is selected from C1-C2 alkyl; n = 0, 3, 4; R 3 is selected from phenyl, naphthyl or substituted phenyl, any one of; R 4 is selected from any one of hydrogen, C1-C3 alkyl, phenyl or substituted phenyl.

[0009] The substituent in the substituted phenyl is selected from any one of ortho, meta or para C1-C5 alkyl, C1-C5 alkoxy, -OCF 3 , halogen, halogenated C1-C5 alkyl, and halogenated C1-C5 alkoxy.

[0010] The substituted phenyl is selected from any one of p-tert-butylbenzene, p-methylbenzene, p-fluorobenzene, p-chlorobenzene, p-bromobenzene, p-iodobenzene, o-methylbenzene, m-methylbenzene, 3,4,5-trifluorotoluene, m-difluorobenzene, 2,4-dimethylbenzene, p-methoxybenzene, trifluoromethoxybenzene.

[0011] Preferably, the α-substituted deuterated amino acid ester compound is selected from the following compounds:

[0012]

[0013] The beneficial effects of the present invention are as follows: The present invention uses readily available amines, aldehyde (ketone) acid esters and deuterated Hantzsch esters as starting materials, and synthesizes deuterated amino acids through reductive amination reaction with the aid of inexpensive calcium catalysts. The method has mild conditions, simple operation, high efficiency and generality, and solves the problems of narrow substrate scope, cumbersome reaction steps and harsh reaction conditions in the prior art. Detailed implementation mode:

[0014] The following is a further description of the present invention, rather than a limitation of the present invention.

[0015] Example 1: Synthesis of ethyl phenylglycinate-2-d (Compound 1)

[0016]

[0017] Add Ca(NTf 2 ) 2 (5 mol%), aniline (0.125 mmol, 1.25 equiv), ethyl glyoxylate (0.1 mmol, 1 equiv), deuterated Hans ester (0.15 mmol, 1.5 equiv) into a 5 mL sealed tube, dissolve them in HFIP (1 ml), and react at 25 °C in an oil bath for 12 hours. After the reaction is completed, use the eluent PE:DCM:EA = 10:20:1 to elute to obtain 15.9 mg of the target product, yield: 88%.

[0018] 1 H NMR (400 MHz, CDCl 3 ): δ 7.89–7.87 (m, 2H), 6.57–6.55 (m, 2H), 4.73 (br, 1H), 4.26 (q, J = 7.2 Hz, 2H), 3.93–3.91 (m, 1H), 3.85 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H).

[0019] 13 C NMR (100 MHz, CDCl 3 ): δ 171.3, 147.12, 129.4, 118.3, 113.1, 61.5, 45.7 (t, J = 21.2), 14.3.

[0020] Example 2: Ethyl (4-(tert-butyl)phenyl)glycinate-2-d (Compound 2)

[0021]

[0022] The preparation method refers to Example 1, using 4-tert-butylaniline as the substrate to obtain 18.4 mg of the target compound, yield: 78%

[0023] 11H NMR (400 MHz, CDCl3): δ 7.24–7.21 (m, 2H), 6.59–6.56 (m, 2H), 4.25 (q, J = 7.1 Hz, 2H), 4.18 (br, 1H), 3.87–3.86 (m, 1H), 1.30 (t, J = 7.2 Hz, 3H), 1.28 (s, 9H).

[0024] 13 13C NMR (100 MHz, CDCl 3 ): δ 171.4, 144.8, 141.1, 126.2, 112.9, 61.4, 45.9 (t, J = 21.2 Hz), 34.0, 31.6, 14.3.

[0025] Example 3: Ethyl (4-fluorophenyl)glycinate-2-d (Compound 3)

[0026]

[0027] The preparation method refers to Example 1, using 4-fluoroaniline as the substrate, and 16.4 mg of the target compound was obtained with a yield of 83%.

[0028] 1 1H NMR (400 MHz, CDCl3): δ 6.92–6.81 (m, 2H), 6.56–6.52 (m, 2H), 4.24 (q, J = 7.1 Hz, 2H), 4.21–4.11 (br, 1H), 3.84 (m, 1H), 1.29 (t, J = 7.1 Hz, 3H).

[0029] 13 13C NMR (100 MHz, CDCl 3 ): δ 171.2, 156.33 (d, J = 235.7 Hz), 143.5, 115.89 (d, J = 22.2 Hz), 113.99 (d, J = 7.5 Hz), 61.5, 46.3 (t, J = 21.0 Hz), 14.3.

[0030] Example 4: Ethyl (4-chlorophenyl)glycinate-2-d (Compound 4)

[0031]

[0032] The preparation method refers to Example 1, using 4-chloroaniline as the substrate, and 17.1 mg of the target compound was obtained with a yield of 80%.

[0033] 11H NMR (400 MHz, CDCl3): δ 7.16–7.11 (m, 2H), 6.54 - 6.50 (m, 2H), 4.30 (br, 1H), 4.24 (q, J = 7.2 Hz, 2H), 3.85 (m, 1H), 1.30 (t, J = 7.2 Hz, 3H).

[0034] 13 13C NMR (100 MHz, CDCl 3 ): δ 171.0, 145.7, 129.3, 122.9, 114.2, 61.6, 45.7 (t, J = 21.2 Hz), 14.3.

[0035] Example 5: Ethyl (4 - bromophenyl)glycinate - 2 - d (Compound 5)

[0036]

[0037] The preparation method refers to Example 1, using 4 - bromoaniline as the substrate, and 22.7 mg of the target compound was obtained with a yield of 88%.

[0038] 1 1H NMR (400 MHz, CDCl3): δ 7.28–7.24 (m, 2H), 6.50–6.46 (m, 2H), 4.32 (br, 1H), 4.24 (q, J = 7.2 Hz, 2H), 3.85–3.83 (m, 1H), 1.30 (t, J = 7.2 Hz, 3H).

[0039] 13 13C NMR (100 MHz, CDCl 3 ): δ 170.9, 146.1, 132.1, 114.6, 110.0, 61.6, 45.5 (t, J = 21.2 Hz), 14.3.

[0040] Example 6: Ethyl (4 - iodophenyl)glycinate - 2 - d (Compound 6)

[0041]

[0042] The preparation method refers to Example 1, using 4 - iodoaniline as the substrate, and 27.5 mg of the target compound was obtained with a yield of 90%.

[0043] 11H NMR (400 MHz, CDCl3): δ 7.45–7.42 (m, 2H), 6.40–6.37 (m, 2H), 4.33 (br, 1H), 4.24 (q, J = 7.1 Hz, 2H), 3.85–3.83 (m, 1H), 1.30 (t, J = 7.1 Hz, 3H).

[0044] 13 13C NMR (100 MHz, CDCl 3 ): δ 170.9, 146.7, 138.0, 115.3, 79.1, 61.6, 45.5 (t, J = 21.2 Hz), 14.3.

[0045] Example 7: Ethyl o -tolylglycinate -2- d (Compound 7)

[0046]

[0047] The preparation method refers to Example 1, using o -toluidine as the substrate, and 15.1 mg of the target compound was obtained, yield: 78%.

[0048] 1 1H NMR (400 MHz, CDCl3): δ 7.15–7.06 (m, 2H), 6.71–6.68 (m, 1H), 6.49–6.47 (m, 1H), 4.26 (q, J = 7.2 Hz, 2H), 4.19 (br, 1H), 3.93–3.91 (m, 1H), 2.22 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H).

[0049] 13 13C NMR (100 MHz, CDCl 3 ): δ 171.4, 145.2, 130.3, 127.2, 122.6, 117.9, 109.9, 61.5, 45.7 (t, J = 21.2 Hz), 21.2, 14.3.

[0050] Example 8: Ethyl m -tolylglycinate -2- d (Compound 8)

[0051]

[0052] The preparation method refers to Example 1, using m -toluidine as the substrate, and 15.7 mg of the target compound was obtained, yield: 81%.

[0053] 11H NMR (400 MHz, CDCl3): δ 7.10–7.07 (m, 1H), 6.59–6.57 (m, 1H), 6.45–6.41 (m, 2H), 4.25 (q, J = 7.2 Hz, 2H), 4.23 (br, 1H) 3.89–3.85 (m, 1H), 2.28 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H).

[0054] 13 13C NMR (100 MHz, CDCl 3 ): δ 171.3, 147.2, 139.2, 129.3, 119.2, 113.9, 110.2, 61.4, 45.7 (t, J = 21.2 Hz), 21.7, 14.3.

[0055] Example 9: Ethyl (3,4,5-trifluorophenyl)glycinate-2-d (Compound 9)

[0056]

[0057] The preparation method refers to Example 1, using 3,4,5-trifluoroaniline as the substrate, and 17.5 mg of the target compound was obtained, yield: 75%.

[0058] 1 1H NMR (400 MHz, CDCl 3 ): δ 6.17–6.13 (m, 2H), 4.39 (br, 1H), 4.25 (q, J = 7.1 Hz, 2H), 3.80–3.78 (m, 1H), 1.30 (t, J = 7.1 Hz, 3H).

[0059] 13 13C NMR (100 MHz, CDCl 3 ): δ 170.4, 153.8 (dd, J = 10.4, 6.0 Hz), 150.8 (dd, J = 10.3, 5.9 Hz), 143.0 (td, J = 11.4, 2.6 Hz), 134.0 (t, J = 15.7 Hz), 131.6 (t, J = 15.7 Hz), 96.8–96.5 (m), 61.8, 45.5 (t, J = 21.2 Hz), 14.3.

[0060] Example 10: Methyl phenylalaninate-2-d (Compound 10)

[0061]

[0062] The preparation method refers to Example 1, using aniline and methyl 2-oxopropionate as the substrates, and 14.9 mg of the target compound was obtained, yield: 83%.

[0063] 1 1H NMR (400 MHz, CDCl3): δ 7.22–7.13 (m, 2H), 6.75 (m, 1H), 6.65–6.57 (m, 2H), 4.17–4.11 (br, 1H), 3.73 (s, 3H), 1.47 (s, 3H).

[0064] 13 13C NMR (100 MHz, CDCl 3 ): δ 175.3, 146.6, 129.5, 118.4, 113.4, 52.3, 51.7 (t, J = 21.2 Hz), 19.0.

[0065] Example 11: Methyl 5-(phenylamino)pentanoate-5-d (Compound 11)

[0066]

[0067] Prepared with reference to Example 1, using aniline and methyl 5-oxopentanoate as substrates, to obtain 18.3 mg of the target compound, yield: 88%.

[0068] 1 1H NMR (400 MHz, CDCl 3 ): δ 7.19–7.15 (m, 2H), 6.71–6.66 (m, 1H), 6.61–6.58 (m, 2H), 3.68 (s, 3H), 3.64 (br, 1H), 3.13–3.09 (m, 1H), 2.37 (t, J = 7.3 Hz, 2H), 1.78–1.70 (m, 2H), 1.67–1.62 (m, 2H).

[0069] 13 13C NMR (100 MHz, CDCl 3 ): δ 174.1, 148.4, 129.4, 117.3, 112.8, 51.7, 43.2 (t, J = 20.6 Hz), 33.8, 28.9, 22.5.

[0070] Example 12: Methyl 6-(phenylamino)hexanoate-6-d (Compound 12)

[0071]

[0072] Prepared with reference to Example 1, using aniline and methyl 6-oxohexanoate as substrates, to obtain 19.3 mg of the target compound, yield: 87%.

[0073] 11H NMR (400 MHz, CDCl 3 ): δ 7.20–7.14 (m, 2H), 6.69 - 6.62 (m, 1H), 6.61–6.58 (m, 2H), 3.67 (s, 3H), 3.61 (br, 1H) 3.10 (m, 3.11–3.07, 1H), 2.34 (t, J = 7.4 Hz, 2H), 1.74–1.57 (m, 4H), 1.51–1.37 (m, 2H).

[0074] 13 13C NMR (100 MHz, CDCl 3 ): δ 174.2, 148.5, 129.3, 117.3, 112.8, 51.7, 43.4 (t, J = 20.7 Hz), 34.1, 29.2, 26.7, 24.8.

[0075] Example 13: Methyl p - Tolylcarbamate - 2 - d (Compound 13)

[0076]

[0077] The preparation method refers to Example 1, using p - toluidine and methyl 2 - oxopropionate as substrates to obtain the target compound 15.8 mg, yield: 82%.

[0078] 1 1H NMR (400 MHz, CDCl3): δ 7.00–6.97 (m, 2H), 6.55–6.51 (m, 2H), 3.99 (br, 1H), 3.72 (s, 3H), 2.23 (s, 3H), 1.45 (s, 3H).

[0079] 13 13C NMR (100 MHz, CDCl 3 ): δ 175.5, 144.3, 130.0, 127.8, 113.7, 52.3, 52.03 (t, J = 21.5 Hz), 20.5, 19.0.

[0080] Example 14: Methyl (4 - (tert - butyl)phenyl)alaninate - 2 - d (Compound 14)

[0081]

[0082] The preparation method refers to Example 1, using 4 - (tert - butyl)aniline and methyl 2 - oxopropionate as substrates to obtain the target compound 20.3 mg, yield: 86%.

[0083] 11H NMR (400 MHz, CDCl3): δ 7.00–6.97 (m, 2H), 6.55–6.51 (m, 2H), 3.99 (br, 1H), 3.72 (s, 3H), 2.23 (s, 3H), 1.45 (s, 9H).

[0084] 13 13C NMR (100 MHz, CDCl 3 ): δ 175.5, 144.2, 141.1, 126.3, 113.1, 52.4, 51.9 (t, J = 21.4 Hz), 34.0, 31.6, 19.1.

[0085] Example 15: Methyl (4-(trifluoromethoxy)phenyl)alaninate-2-d (Compound 15)

[0086]

[0087] The preparation method refers to Example 1, using 4-(trifluoromethoxy)aniline and methyl 2-oxopropionate as substrates, and 29.8 mg of the target compound was obtained with a yield of 86%.

[0088] 1 1H NMR (400 MHz, CDCl3): δ 7.08–6.97 (m, 2H), 6.61–6.51 (m, 2H), 4.21 (br, 1H), 3.74 (s, 3H), 1.47 (s, 3H).

[0089] 13 13C NMR (100 MHz, CDCl 3 ): δ 174.9, 145.4, 141.1 (q, J = 2.1 Hz), 122.6, 120.74 (q, J = 255.3 Hz), 113.7, 52.5, 52.0, 51.8, 51.6, 18.8.

[0090] Example 16: Methyl naphthalen-2-ylalaninate-2-d (Compound 16)

[0091]

[0092] The preparation method refers to Example 1, using naphthalen-2-amine and methyl 2-oxopropionate as substrates, and 20.2 mg of the target compound was obtained with a yield of 88%.

[0093] 11H NMR (400 MHz, CDCl3): δ 7.69–7.60 (m, 3H), 7.38–7.34 (m, 1H), 7.24–7.20 (m, 1H), 6.93–6.90 (m, 1H), 6.77–6.76 (m, 1H), 4.33 (br, 1H), 3.75 (s, 3H), 1.54 (s, 3H).

[0094] 13 13C NMR (100 MHz, CDCl 3 ): δ 175.2, 144.3, 135.1, 129.3, 128.0, 127.7, 126.5, 126.2, 122.5, 118.2, 105.4, 52.4, 51.8 (t, J = 21.4 Hz), 18.8.

[0095] Example 17: Methyl o -tolylalaninate-2-d (Compound 17)

[0096]

[0097] The preparation method refers to Example 1, using o -toluidine and methyl 2-oxopropionate as substrates to obtain 17.4 mg of the target compound with a yield of 90%.

[0098] 1 1H NMR (400 MHz, CDCl3): δ 7.11–7.05 (m, 2H), 6.71–6.66 (m, 1H), 6.52–6.50 (m, 1H), 4.04 (br, 1H), 3.74 (s, 3H), 2.20 (s, 3H), 1.51 (s, 3H).

[0099] 13 13C NMR (100 MHz, CDCl 3 ): δ 175.5, 144.7, 130.5, 127.2, 122.7, 118.0, 110.3, 52.4, 51.6 (t, J = 21.7 Hz), 19.2, 17.6.

[0100] Example 18: Methyl m -tolylalaninate-2-d (Compound 18)

[0101]

[0102] The preparation method refers to Example 1, using m -toluidine and methyl 2-oxopropionate as substrates to obtain 17.0 mg of the target compound with a yield of 88%.

[0103] 11H NMR (400 MHz, CDCl3): δ 7.06–7.04 (m, 1H), 6.57–6.55 (m, 1H), 6.43–6.39 (m, 2H), 4.09 (br, 1H), 3.73 (s, 3H), 2.26 (s, 3H), 1.46 (s, 3H).

[0104] 13 13C NMR (100 MHz, CDCl 3 ): δ 175.4, 146.6, 139.3, 129.3, 119.4, 114.3, 110.5, 52.4, 51.7 (t, J = 21.8 Hz), 21.7, 19.0.

[0105] Example 19: Methyl (2,4-dimethylphenyl)alaninate-2-d (Compound 19)

[0106]

[0107] The preparation method refers to Example 1, using 2,4-dimethylaniline and methyl 2-oxopropionate as substrates to obtain 17.3 mg of the target compound, yield: 83%.

[0108] 1 1H NMR (400 MHz, CDCl3): δ 6.90–6.87 (m, 2H), 6.44–6.42 (m, 1H), 3.90 (br, 1H), 3.73 (s, 3H), 2.22 (s, 3H), 2.18 (s, 3H), 1.49 (s, 3H).

[0109] 13 13C NMR (100 MHz, CDCl 3 ): δ 175.6, 142.4, 131.4, 127.4, 127.2, 123.0, 110.6, 52.3, 51.9 (t, J = 21.8 Hz), 20.5, 19.2, 17.6.

[0110] Example 20: Ethyl 2-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)acetate-2-d (Compound 20)

[0111]

[0112] The preparation method refers to Example 1, using 10,11-dihydro-5H-dibenzo[b,f]azepine as the substrate to obtain 24.8 mg of the target compound, yield: 88%.

[0113] 1 1H NMR (400 MHz, CDCl3 ): δ 7.13–7.08 (m, 4H), 7.05–6.98 (m, 2H), 6.97–6.87 (m, 2H), 4.53 (br, 1H), 4.11 (q, J = 7.1 Hz, 2H), 3.22 (s, 4H), 1.14 (t, J = 7.1 Hz, 3H).

[0114] 13 C NMR (100 MHz, CDCl 3 ): δ 170.5, 147.7, 134.5, 130.1, 126.7, 123.0, 119.7, 61.1, 54.9 (t, J = 20.7 Hz), 32.7, 14.2.

[0115] Example 21: Ethyl 2-(2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)acetate-2-d (Compound 21)

[0116]

[0117] The preparation method refers to Example 1, using 2,3,4,5-tetrahydro-1H-benzo[b]azepine as the substrate to obtain 20.6 mg of the target compound, yield: 78%.

[0118] 1 H NMR (400 MHz, CDCl3): δ 7.10 (m, 2H), 6.87–6.83 (m, 1H), 6.80–6.74 (m, 1H), 4.23 (q, J = 7.1 Hz, 2H), 3.96 (s, 1H), 3.10 (t, J = 5.5 Hz, 2H), 2.81 (t, J = 5.5 Hz, 2H,), 1.79 (m, 2H), 1.71–1.56 (m, 2H), 1.29 (t, J = 7.1 Hz, 3H).

[0119] 13 C NMR (100 MHz, CDCl 3 ): δ 171.9, 151.1, 135.5, 130.4, 126.7, 121.4, 117.4, 60.8, 56.3 (t, J = 20.8 Hz), 54.8, 35.1, 29.7, 25.7, 14.4.

[0120] Example 22: Ethyl N-(4-methoxyphenyl)-N-methylglycinate-2-d (Compound 22)

[0121]

[0122] The preparation method refers to Example 1. Using 4-methoxy-N-methylaniline as the substrate, the target compound (20.8 mg) was obtained with a yield of 93%.

[0123] 1 H NMR (400 MHz, CDCl3): δ 6.88–6.79 (m, 2H), 6.72–6.65 (m, 2H), 4.16 (q, J = 7.2 Hz, 2H), 3.98 (s, 1H), 3.75 (s, 3H), 3.01 (s, 3H), 1.23 (t, J = 7.1 Hz, 3H).

[0124] 13 C NMR (100 MHz, CDCl 3 ): δ 171.3, 152.2, 143.7, 114.8, 114.2, 60.8, 55.8, 55.2 (t, J = 21.9 Hz), 40.1, 14.3

[0125] Example 23: Ethyl N-(4-chlorophenyl)-N-methylglycinate-2-d (Compound 23)

[0126]

[0127] The preparation method refers to Example 1. Using 4-chloro-N-methylaniline as the substrate, the target compound (20.7 mg) was obtained with a yield of 91%.

[0128] 1 H NMR (400 MHz, CDCl3): δ 7.22–7.08 (m, 2H), 6.65–6.53 (m, 2H), 4.17 (q, J = 7.2 Hz, 2H), 4.01 (s, 1H), 3.04 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H).

[0129] 13 C NMR (100 MHz, CDCl 3 ): δ 170.8, 147.6, 129.1, 122.3, 113.5, 61.1, 54.3 (t, J = 21.9 Hz), 39.7, 14.3.

[0130] Example 24: Ethyl N-phenyl-N-(p-tolyl)glycinate-2-d (Compound 24)

[0131]

[0132] The preparation method refers to Example 1. Using 4-methyl-N-phenylaniline as the substrate, the target compound (23.8 mg) was obtained with a yield of 88%.

[0133] 1 1H NMR (400 MHz, CDCl 3 ): δ 7.32–7.17 (m, 2H), 7.15–7.09 (m, 2H), 7.05–6.99 (m, 2H), 6.94–6.80 (m, 3H), 4.39 (s, 1H), 4.19 (q, J = 7.1 Hz, 2H), 2.32 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H).

[0134] 13 13C NMR (100 MHz, CDCl 3 ): δ 171.1, 147.9, 144.9, 132.9, 130.2, 129.2, 123.2, 120.4, 118.2, 61.1, 54.0 (t, J = 21.9 Hz), 20.9, 14.3.

[0135] Example 25: Ethyl N-phenyl-N-(o-tolyl)glycinate-2-d (Compound 25)

[0136]

[0137] The preparation method refers to Example 1, using 2-methyl-N-phenylaniline as the substrate to obtain 22.4 mg of the target compound, with a yield of 83%.

[0138] 1 1H NMR (400 MHz, CDCl 3 ): δ 7.38–7.36 (m, 1H), 7.33–7.27 (m, 1H), 7.26–7.12 (m, 4H), 6.76–6.71 (m, 1H), 6.45–6.43 (m, 2H), 4.31 (s, 1H), 4.22 (q, J = 7.1 Hz, 2H), 2.19 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H).

[0139] 13 13C NMR (100 MHz, CDCl 3 ): δ 171.1, 147.8, 145.1, 137.1, 131.5, 129.4, 129.2, 127.7, 127.0, 117.7, 112.9, 61.2, 53.7 (t, J = 20.9 Hz), 18.0, 14.3.

[0140] Example 26: Ethyl (3,5-difluorophenyl)glycinate-2-d (Compound 26)

[0141]

[0142] The preparation method refers to Example 1. Using 3,5-difluoroaniline as the substrate, 19.0 mg of the target compound was obtained, with a yield of 88%.

[0143] 1 H NMR (400 MHz, CDCl 3 ): δ 6.23–6.12 (m, 1H), 6.10–6.06 (m, 2H), 4.54 (s, 1H), 4.26 (q, J = 7.2 Hz, 2H), 3.84–3.82 (m, 1H), 1.31 (t, J = 7.2 Hz, 3H).

[0144] 13 C NMR (100 MHz, CDCl 3 ): δ 170.5, 165.5 (d, J = 15.9 Hz), 163.0 (d, J = 15.9 Hz), 149.3 (t, J = 13.5 Hz), 96.4–95.1 (m), 93.3 (t, J = 13.5 Hz), 61.8, 45.3 (t, J = 21.2 Hz), 14.3.

[0145] Example 27: Ethyl N,N-diphenylglycinate-2-d (Compound 27)

[0146]

[0147] The preparation method refers to Example 1. Using diphenylamine as the substrate, 20.8 mg of the target compound was obtained, with a yield of 81%.

[0148] 1 H NMR (400 MHz, CDCl 3 ): δ 7.33–7.19 (m, 5H), 7.05–6.89 (m, 5H), 4.43–4.42 (m, 1H), 4.20 (q, J = 7.1 Hz, 2H), 1.28–1.23 (m, 3H).

[0149] 13 C NMR (100 MHz, CDCl 3 ): δ 171.05, 147.55, 129.45, 122.03, 120.79, 61.24, 53.98 (t, J = 21.5 Hz), 14.34.

[0150] Example 28: (Compound 28)

[0151]

[0152] The preparation method refers to Example 1. Using iminobis(p-trifluoromethylphenyl)-λ 6 -sulfone as the substrate, 41.1 mg of the target compound was obtained, with a yield of 83%.

[0153] 1 H NMR (400 MHz, CDCl 3 ): δ 7.70 (s, 1H), 7.37 (dd, J = 7.8, 1.7 Hz, 1H), 7.21 (dd, J = 7.9, 1.3 Hz, 1H), 7.14–7.10 (m, 1H), 7.05–7.01 (m, 1H), 5.39 (s, 1H), 4.79–4.66 (m, 2H), 4.20 (q, J = 7.2 Hz, 2H), 4.07–3.99 (m, 2H), 3.65–3.62 (m, 2H), 3.60 (s, 3H), 3.44 (s, 1H), 2.90–2.88 (m, 2H), 2.33 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H), 1.17 (t, J = 7.1 Hz, 3H).

[0154] 13 C NMR (100 MHz, CDCl 3 ): δ 171.19, 144.79, 135.11, 129.26, 127.93, 127.79, 126.54, 126.14, 122.49, 118.04, 104.84, 61.59, 45.91, 45.70, 45.49, 14.36.

[0155] Example 29: (Compound 29)

[0156]

[0157] The preparation method refers to Example 1. Using 4-amino-N-(5-methylisoxazol-3-yl)benzenesulfonamide as the substrate, 29.6 mg of the target compound was obtained, with a yield of 87%.

[0158] 1 H NMR (400 MHz, CDCl 3 ): δ 7.75–7.72 (m, 2H), 7.31–7.28 (m, 2H), 4.22–4.16 (m, 2H), 3.99 (br, 2H), 3.34–3.33 (m, 1H), 3.06–3.03 (m, 2H), 2.71–2.67 (m, 2H), 2.42 (s, 3H), 1.67–1.60 (m, 2H), 1.29–1.24 (m, 3H).

[0159] 1313C NMR (100 MHz, CDCl 3 ): δ 172.12, 143.40, 137.04, 129.81, 127.22, 61.30, 50.13 (t, J = 21.0 Hz), 48.04, 42.83, 28.17, 21.65, 14.30.

[0160] Example 30: (Compound 30)

[0161]

[0162] The preparation method refers to Example 1, using iminobis (p - formylcarbonyloxyphenyl)-λ 6 -sulfone as the substrate to obtain 26.8 mg of the target compound, yield: 79%.

[0163] 1 1H NMR (400 MHz, CDCl 3 ): δ 7.65–7.59 (m, 2H), 6.56–6.50 (m, 2H), 6.19–6.18 (m, 1H), 4.91–4.90 (m, 1H), 4.25 (t, J = 7.2 Hz, 2H), 3.89–3.88 (m, 1H), 2.34 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H).

[0164] 13 13C NMR (100 MHz, CDCl 3 ): δ 170.9, 170.2, 157.7, 151.0, 129.4, 126.3, 112.2, 95.6, 62.0, 44.6 (t, J = 21.2 Hz), 29.8, 14.2, 12.8.

Claims

1. A method for synthesizing an α-substituted deuterated amino acid ester compound, characterized in that: The method comprises the following steps: using amine, aldehydic acid ester or ketoic acid ester and deuterated Hans ester as starting materials, and using Ca(NTf2)2 as a catalyst to synthesize by reductive amination reaction; the formula is as follows: In the formula, R 1 Any one selected from hydrogen, C1-C2 alkyl, halogen; R 2 Selected from C1-C2 alkyl; n=0,3,4; R 3 is selected from phenyl, naphthyl or phenyl with a substituent, Any of R 4 Any one selected from hydrogen, C1-C3 alkyl, phenyl or phenyl with a substituent; the substituent in the phenyl with a substituent is selected from any one of ortho-, meta- or para-positioned C1-C5 alkyl, C1-C5 alkoxy, -OCF3, halogen, halogenated C1-C5 alkyl, halogenated C1-C5 alkoxy.

2. The method for synthesizing the α-substituted deuterated amino acid ester compound according to claim 1, characterized in that: The substituted phenyl group is selected from any one of p-tert-butylbenzene, p-methylbenzene, p-fluorobenzene, p-chlorobenzene, p-bromobenzene, p-iodobenzene, o-methylbenzene, m-methylbenzene, 3,4,5-trifluorotoluene, m-difluorobenzene, 2,4-dimethylbenzene, p-methoxybenzene and trifluoromethoxybenzene.

3. The method for synthesizing the α-substituted deuterated amino acid ester compound according to claim 1, characterized in that: The α-substituted deuterated amino acid ester compound is selected from the following compounds:

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