Preparation method of 2,3-diaminopropionic acid derivatives with three different amino groups

Abstract

The present invention belongs to the field of organic chemistry, and particularly relates to a preparation method of 2,3-diaminopropionic acid derivatives with different amino groups at the 3-position. The preparation method of 2,3-diaminopropionic acid derivatives with different amino groups at the 3-position provided by the present invention uses L-serine as a raw material, reacts with phthalic anhydride under the catalysis of triethylamine to obtain compound 2, and then performs a Michael addition reaction with amines to obtain 2,3-diaminopropionic acid derivatives with different amino groups at the 3-position. The synthesis method provided by the present invention has simple steps and a high reaction yield. At the same time, the raw materials involved in the present invention are easily available and the reaction conditions are mild.

Description

Technical Field

[0001] The present invention belongs to the field of organic chemistry, and particularly relates to a preparation method of 2,3-diaminopropionic acid derivatives having different amino groups at the 3-position. Background Art

[0002] Currently, non-natural di-amino acids have more and more uses in the fields of drug synthesis, biomimetic synthesis, etc. Among them, 2,3-diaminopropionic acid is an important category. A large number of literature reports have been made on 2,3-diaminopropionic acid with hydrocarbon group substitution on the amino group at the 3-position. Pleixates reported that methyl-2-amidoacrylate undergoes addition reaction with cyclic amine under the catalysis of ferric chloride, and then hydrolysis can obtain 2,3-diaminopropionic acid derivatives substituted by piperidine and morpholine at the 3-position. However, the raw material methyl-2-amidoacrylate is expensive, and it is not suitable for non-cyclic amines 1 . Abe synthesized 2,3-diaminopropionic acid derivatives substituted by nitrogen at the 3-position through Mannich reaction of diethyl formamidomalonate with different secondary amines as raw materials, but the raw material diethyl formamidomalonate used in this reaction is relatively expensive 2 . Belokon used chiral nickel complex as the starting material to react with formaldehyde and amine to generate chiral 2,3-diaminopropionic acid derivatives, but the process of synthesizing the chiral nickel complex in this method is complex and not convenient for industrial use 3,4 . Peregrina synthesized 2,3-diaminopropionic acid derivatives substituted by nitrogen at the 3-position through Michael addition using chiral bicyclic dehydroalanine as the raw material. This method can synthesize chiral amino acids, but the synthetic route of the starting material chiral bicyclic dehydroalanine is complex and not convenient for large-scale use 5 . Schneider synthesized nitrogen-substituted 2,3-diaminopropionic acid derivatives through nitrogen-protected serine lactone, but another raw material needs to use organosilicon compounds, and the reaction generality is not high 6 . Summary of the Invention

[0003] In order to solve the problems of high raw material price, complex synthesis process, low reaction generality, etc. of the existing methods, the present invention provides a preparation method of 2,3-diaminopropionic acid derivatives having different amino groups at the 3-position. The method provided by the present invention uses L-serine as the raw material, reacts with phthalic anhydride under the catalysis of triethylamine to obtain compound 2, and then performs Michael addition reaction with amines to obtain 2,3-diaminopropionic acid derivatives. The amines are any one of C1-C4 alkylamines, ; wherein, R1-R4 are independently -H, halogen, -CF3, -OCH3 or C1-C4 alkyl.

[0004] The reaction formula for the preparation method of the above-mentioned 2,3-diaminopropionic acid derivatives with different amino groups at the 3-position is as follows:

[0005]

[0006] Among them, R is any one of C1-C4 alkylamino, ; among them, R1-R4 are independently -H, halogen, -CF3, -OCH3 or C1-C4 alkyl.

[0007] The preparation method of the 2,3-diaminopropionic acid derivatives with different amino groups at the 3-position includes the following steps:

[0008] a. Dissolve L-serine and phthalic anhydride in toluene, add triethylamine, and reflux for 2-6 h; after the reaction is completed, remove the solvent from the reactants, dissolve in dichloromethane, first remove the unreacted L-serine completely, and then through extraction, combine the organic phases, dry, concentrate, and perform column chromatography to obtain compound 2;

[0009] b. Dissolve compound 2 and amines in a solvent, add an acetic acid catalyst, heat to 25-105 °C and stir for 1-24 h. After the reaction is completed, concentrate the reaction solution and perform column chromatography to obtain the 2,3-diaminopropionic acid derivative.

[0010] In the preparation method of the 2,3-diaminopropionic acid derivatives with different amino groups at the 3-position, the molar ratio of L-serine, phthalic anhydride and triethylamine in step a is 1:1:0.1.

[0011] In the preparation method of the 2,3-diaminopropionic acid derivatives with different amino groups at the 3-position, the eluent for column chromatography in step a is a mixed solvent of PE (petroleum ether) and EA (ethyl acetate), and their volume ratio is 5-10:1-3. 5‰ of acetic acid based on the total volume of the eluent is also added to the eluent.

[0012] In the preparation method of the 2,3-diaminopropionic acid derivatives with different amino groups at the 3-position, the method for removing the unreacted L-serine completely in step a is to wash the reactants dissolved in dichloromethane with 1M hydrochloric acid aqueous solution for 1-3 times.

[0013] In the preparation method of the 2,3-diaminopropionic acid derivatives with different amino groups at the 3-position, the molar ratio of compound 2, amines and catalyst in step b is 1:0.5-2:0.2-2.

[0014] In the preparation method of the 2,3-diaminopropionic acid derivatives with different amino groups at the 3-position, the catalyst in step b is any one of trifluoroacetic acid, p-toluic acid, phosphoric acid, hydrochloric acid, propionic acid or acetic acid.

[0015] The preparation method of the 2,3-diaminopropionic acid derivative with different amino groups at the 3-position, the organic solvent described in step b is any one of toluene, acetonitrile, methanol, dichloromethane, DMF (N,N-dimethylformamide) or water.

[0016] The preparation method of the 2,3-diaminopropionic acid derivative with different amino groups at the 3-position, the eluent for column chromatography described in step b is a mixed solvent of DCM (dichloromethane) and MeOH (methanol), and the volume ratio is 10-20:1. 5‰ of acetic acid based on the total volume of the eluent is also added to the eluent; or it is a mixed solvent of PE and EA, and the volume ratio is 5-10:1-3. 5‰ of acetic acid based on the total volume of the eluent is also added to the eluent.

[0017] The present invention uses L-serine as a raw material, reacts with phthalic anhydride under the catalysis of triethylamine to obtain acrylic acid substituted by phthalimide at the 2-position, and then performs a Michael addition reaction with amines to obtain a 2,3-diaminopropionic acid derivative with different amino groups at the 3-position. The synthesis method provided by the present invention has simple steps and a high reaction yield. When performing the Michael addition in the second step of the synthesis, the highest yield reaches 96.1%. At the same time, the raw materials involved in the present invention are easily available, the reaction conditions are mild, no dangerous operations are required, and no extreme conditions such as high temperature and high pressure are involved, which is convenient for later scale-up production. Specific embodiments

[0018] The preparation method of the 2,3-diaminopropionic acid derivative with different amino groups at the 3-position includes the following steps:

[0019] a. Dissolve L-serine and phthalic anhydride in toluene, add triethylamine, and reflux for 2-6 h; after the reaction is completed, remove the solvent, add dichloromethane to dissolve, first wash with 1M hydrochloric acid aqueous solution to remove the unreacted L-serine completely, and then through extraction, combining the organic phases, drying, and concentration, column chromatography to obtain compound 2; the molar ratio of L-serine, phthalic anhydride and triethylamine is 1:1:0.11;

[0020] b. Dissolve compound 2 and amines in a solvent, add an acetic acid catalyst, heat to 25-105 °C and stir for 1-24 h. After the reaction is completed, concentrate the reaction solution, and column chromatography to obtain a 2,3-diaminopropionic acid derivative; the molar ratio of compound 2, amines and the catalyst is 1:0.5-2:0.2-2; the catalyst is any one of trifluoroacetic acid, p-toluic acid, phosphoric acid, hydrochloric acid, propionic acid or acetic acid.

[0021] The preparation method of the 2,3-diaminopropionic acid derivative with different amino groups at the 3-position. In step a, the eluent for column chromatography is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio is 5-10:1-3. 5‰ of acetic acid based on the total volume of the eluent is also added to the eluent.

[0022] The preparation method of the 2,3-diaminopropionic acid derivative with different amino groups at the 3-position. In step a, the number of washing times is 1-3 times.

[0023] The preparation method of the 2,3-diaminopropionic acid derivative with different amino groups at the 3-position. In step b, the organic solvent is any one of toluene, acetonitrile, methanol, dichloromethane, DMF or water.

[0024] The preparation method of the 2,3-diaminopropionic acid derivative with different amino groups at the 3-position. In step b, the eluent for column chromatography is a mixed solvent of DCM and MeOH, and the volume ratio is 10-20:1. 5‰ of acetic acid based on the total volume of the eluent is also added to the eluent; or it is a mixed solvent of PE and EA, and the volume ratio is 5-10:1-3. 5‰ of acetic acid based on the total volume of the eluent is also added to the eluent.

[0025] Synthesis of Compound 2 in Example 1

[0026]

[0027] L-serine (24 mmol, 2.5 g) and phthalic anhydride (24 mmol, 3.5 g) were added to a 500 mL round-bottom flask, dissolved in 250 mL of toluene, triethylamine (5.2 mmol, 355 μL) was added, and the mixture was heated under reflux at 105 °C for 4 h using a Dean-Stark apparatus. After the reaction was completed, the solvent was evaporated, dissolved in dichloromethane, washed with 1 M hydrochloric acid aqueous solution to remove the unreacted L-serine, and the aqueous phase was extracted three times with ethyl acetate. All the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the obtained compound 2 was obtained by column chromatography (PE:EA = 7:3, 5‰ acetic acid) as a white solid. It had fluorescence at 254 nm and the yield was 42.23%.

[0028] 1 H NMR (400 MHz, CHCl3-d) δ 7.92 (q, 2H, -pht), 7.78 (q, 2H, -pht), 6.83, 6.12 (s, 2H, CH2). 13 C NMR (100 MHz, CHCl3-d) δ 167.09, 166.35, 134.60, 131.72, 130.71, 128.54, 124.04. HR-MS [M+H] +216.0403 (Theoretical value: 216.0302).

[0029] Example 2 Synthesis of 2,3-diaminopropionic acid derivatives (3a - 3w)

[0030] (1) Synthesis of 2,3-diaminopropionic acid derivative 3a

[0031]

[0032] Compound 2 (0.469 mmol, 0.1 g) and piperidine (0.704 mmol, 70 μL) were added to a 100 mL round-bottom flask, dissolved in 10 mL of toluene, acetic acid (0.469 mmol, 27 μL) was added, and the mixture was heated to 65 °C and stirred for 12 h. After the reaction was completed, the reaction solution was concentrated. Column chromatography (DCM∶MeOH = 10∶1, 5‰ acetic acid) gave 2,3-diaminopropionic acid derivative 3a with different amino groups at the 3-position as a white solid. It fluoresced at 254 nm, developed color with ninhydrin, and the yield was 85%.

[0033] 1 H NMR (400 MHz, DMSO-d6) δ 7.90 (m, 4H, -pht), 4.79 (t, 1H, CH), 3.34–3.20 (m, 2H, CH2), 2.84 (s, 4H, N(CH2)2), 1.55–1.43 (m, 6H, CH2CH2CH2).

[0034] 13 C NMR (100 MHz, DMSO-d6) δ 169.31, 168.06, 135.14, 131.98, 123.67, 55.55, 52.94, 48.02, 24.59, 22.84.

[0035] HR-MS [M + H] + 303.1332 (Theoretical value: 303.1339).

[0036] (2) Synthesis of 2,3-diaminopropionic acid derivative 3b

[0037]

[0038] Compound 2 (0.469 mmol, 0.1 g) and pyrrolidine (0.704 mmol, 58 μL) were added to a 100 mL round-bottom flask, dissolved in 10 mL of toluene, acetic acid (0.469 mmol, 27 μL) was added, and the mixture was stirred at 65 °C for 12 h. After the reaction was completed, the solvent was evaporated, and the reaction solution was concentrated. Column chromatography (DCM∶MeOH = 10∶1, 5‰ acetic acid) gave 2,3-diaminopropionic acid derivative 3b with different amino groups at the 3-position as a white solid. It fluoresced at 254 nm and gave a color reaction with ninhydrin, with a yield of 79%.

[0039] 1 H NMR (400 MHz, DMSO-d6) δ 7.90 (m, 4H, -pht), 4.62 (t, 1H, CH), 3.68–3.50 (m, 2H, CH2), 3.12 (s, 4H, N(CH2)2), 1.85 (s, 4H, CH2CH2).

[0040] HR-MS [M+H] + 289.1177 (theoretical value: 289.1183).

[0041] (3) Synthesis of 2,3-diaminopropionic acid derivative 3c

[0042]

[0043] Compound 2 (0.469 mmol, 0.1 g) and morpholine (0.704 mmol, 62 μL) were added to a 100 mL round-bottom flask, dissolved in 10 mL of toluene. Acetic acid (0.469 mmol, 27 μL) was added, and the mixture was stirred at 65 °C for 12 h. After the reaction was completed, the solvent was evaporated, and the reaction solution was concentrated. Column chromatography (DCM∶MeOH = 10∶1, 5‰ acetic acid) gave 2,3-diaminopropionic acid derivative 3c with different amino groups at the 3-position as a white solid. It fluoresced at 254 nm and gave a color reaction with ninhydrin, with a yield of 70.9%.

[0044] 1 H NMR (400 MHz, DMSO-d6) δ 7.90 (m, 4H, -pht), 4.92 (q, 1H, CH), 3.41 (s, 4H, O(CH2)2), 3.16, 2.91 (m, 2H, CH2), 2.53, 2.30 (m, 4H, N(CH2)2).

[0045] 13 C NMR (100 MHz, DMSO-d6) δ 170.39, 167.90, 135.28, 131.67, 123.80, 66.50, 56.26, 53.25, 49.54.

[0046] HR-MS [M+H] + 305.1264 (theoretical value: 305.1132).

[0047] (4) Synthesis of 2,3-diaminopropionic acid derivative 3d

[0048]

[0049] Compound 2 (0.469 mmol, 0.1 g) was added to a 100 mL round-bottom flask, followed by diethylamine (0.704 mmol, 73 μL). 10 mL of toluene was added to dissolve the mixture, and then acetic acid (0.469 mmol, 27 μL) was added. The reaction was carried out at 65 °C for 12 h. After the reaction was completed, the solvent was removed by rotary evaporation. Column chromatography (DCM∶MeOH = 10∶1, 5‰ acetic acid) was used to obtain 2,3-diaminopropionic acid derivative 3d with different amino groups at the 3-position as a white solid. It fluoresced at 254 nm and developed color with ninhydrin, with a yield of 74.5%.

[0050] 1 H NMR (400 MHz, DMSO-d6) δ 7.90 (m, 4H, -pht), 4.72 (t, 1H, CH), 3.47–3.27 (m, 2H, CH2), 2.94 (m, 4H, N(CH2)2), 1.08 (t, 6H, (CH3)2).

[0051] 13 C NMR (100 MHz, DMSO-d6) δ 169.39, 168.06, 135.16, 131.96, 123.66, 50.38, 46.66, 10.54.

[0052] HR-MS [M+H] + 291.1334 (theoretical value: 291.1339).

[0053] (5) Synthesis of 2,3-diaminopropionic acid derivative 3e

[0054]

[0055] Compound 2 (0.469 mmol, 0.1 g) was added to a 100 mL round-bottom flask, and then ethylamine (0.704 mmol, 39.2 μL) was added dropwise. 10 mL of toluene was added for dissolution. Acetic acid (0.469 mmol, 27 μL) was added, and the mixture was heated to 65 °C and stirred for 12 h. After the reaction was completed, the solvent was removed by rotary evaporation, and column chromatography (DCM∶MeOH = 10∶1, 5‰ acetic acid) was performed to obtain 2,3-diaminopropionic acid derivative 3e with different amino groups at the 3-position, which was a white solid. It had fluorescence at 254 nm and developed color with ninhydrin, and the yield was 56.1%.

[0056] 1 H NMR (400 MHz, DMSO-d6) δ 7.87 (m, 4H, -pht), 4.49 (t, 1H, CH), 3.61, 3.31 (m, 2H, CH2), 2.99 (m, 2H, NCH2), 1.14 (m, 3H, CH3).

[0057] 13 C NMR (100 MHz, DMSO-d6) δ 168.33, 134.95, 132.32, 123.50, 49.47, 46.06, 11.76.

[0058] HR-MS [M+H] + 263.1020 (theoretical value: 263.1026).

[0059] (6) Synthesis of 2,3-diaminopropionic acid derivative 3f

[0060]

[0061] Compound 2 (0.469 mmol, 0.1 g) was added to a 100 mL round-bottom flask, and then hexamethyleneimine (0.704 mmol, 79.34 μL) was added. 10 mL of toluene was added for dissolution. Acetic acid (0.469 mmol, 27 μL) was added, and the mixture was heated to 65 °C and stirred for 12 h. After the reaction was completed, the solvent was removed by rotary evaporation, and column chromatography (DCM∶MeOH = 10∶1, 5‰ acetic acid) was performed to obtain 2,3-diaminopropionic acid derivative 3f with different amino groups at the 3-position, which was a white solid. It had fluorescence at 254 nm and developed color with ninhydrin, and the yield was 60%.

[0062] 1 H NMR (400 MHz, DMSO-d6) δ 7.90 (m, 4H, -pht), 4.70 (t, 1H, CH), 3.51, 3.35 (m, 2H, CH2), 3.08 (m, 4H, N(CH2)2), 1.68, 1.52 (m, 8H).

[0063] 13 13C NMR (100 MHz, DMSO-d6) δ 169.49, 168.08, 135.17, 131.96, 123.66, 55.25, 54.16, 45.46, 26.54, 25.85, 25.04.

[0064] HR-MS [M+H] + 317.1491 (theoretical value: 317.1496).

[0065] (7) Synthesis of 2,3-diaminopropionic acid derivative 3g

[0066]

[0067] Compound 2 (0.469 mmol, 0.1 g) was added to a 100 mL round-bottom flask, then thiazolidine (0.704 mmol, 56 μL) was added dropwise, 10 mL of toluene was added for dissolution, acetic acid (0.469 mmol, 27 μL) was added, and the mixture was heated to 65 °C and stirred for 12 h. After the reaction was completed, the solvent was removed by rotary evaporation, and column chromatography (DCM∶MeOH = 10∶1, 5‰ acetic acid) was carried out to obtain 2,3-diaminopropionic acid derivative 3g with different amino groups at the 3-position, which was a white solid. It had fluorescence at 254 nm, developed color with ninhydrin, and the yield was 60%.

[0068] 1 1H NMR (400 MHz, DMSO-d6) δ 7.92 (m, 4H, -pht), 5.06 (t, 1H, CH), 4.10, 3.83 (m, 2H, CH2), 3.03–2.73 (m, 6H, -Thiazolidine).

[0069] 13 13C NMR (100 MHz, DMSO-d6) δ 169.95, 167.78, 135.46, 131.51, 123.97, 60.83, 58.00, 51.38, 51.02, 29.38.

[0070] HR-MS [M+H] + 307.0744 (theoretical value: 307.0747).

[0071] (8) Synthesis of 2,3-diaminopropionic acid derivative 3h

[0072]

[0073] Compound 2 (0.469 mmol, 0.1 g) was added to a 100 mL round-bottom flask, then thiomorpholine (0.704 mmol, 71 μL) was added dropwise. 10 mL of toluene was added to dissolve the mixture, and acetic acid (0.469 mmol, 27 μL) was added. The mixture was heated to 65 °C and stirred for 12 h. After the reaction was completed, the solvent was removed by rotary evaporation, and column chromatography (DCM∶MeOH = 10∶1, 5‰ acetic acid) was carried out to obtain 2,3-diaminopropionic acid derivative 3h with different amino groups at the 3-position, which was a white solid. It had fluorescence at 254 nm, developed color with ninhydrin, and the yield was 65%.

[0074] 1 H NMR (400 MHz, DMSO-d6) δ 7.92 (m, 4H, -pht), 5.02 (t, 1H, CH), 3.08, 3.00 (m, 2H, CH2), 2.80 (m, 6H, -Thiazolidine), 2.80 - 2.56 (m, 4H, N(CH2)2), 2.39 (m, 4H, S(CH2)2).

[0075] 13 C NMR (100 MHz, DMSO-d6) δ 170.17, 167.82, 135.39, 131.58, 123.88, 56.15, 54.60, 49.40, 27.59.

[0076] HR-MS [M+H] + 321.0902 (theoretical value: 321.0904).

[0077] (9) Synthesis of 2,3-diaminopropionic acid derivative 3i

[0078]

[0079] Compound 2 (0.469 mmol, 0.1 g) was added to a 100 mL round-bottom flask, then 3-methylpiperidine (0.704 mmol, 83 μL) was added dropwise. 10 mL of toluene was added to dissolve the mixture, and acetic acid (0.469 mmol, 27 μL) was added. The mixture was heated to 65 °C and stirred for 12 h. After the reaction was completed, the solvent was removed by rotary evaporation, and column chromatography (DCM∶MeOH = 10∶1, 5‰ acetic acid) was carried out to obtain 2,3-diaminopropionic acid derivative 3i with different amino groups at the 3-position, which was a white solid. It had fluorescence at 254 nm, developed color with ninhydrin, and the yield was 61.5%.

[0080] 11H NMR (400 MHz, DMSO-d6) δ 7.90 (m, 4H, -pht), 4.82 (t, 1H, CH), 4.10, 3.83 (m, 2H, CH2), 3.32–3.13 (m, 6H, N(CH2)3), 1.65 (t, 2H, NCH2CH2), 1.42, 0.96 (m, 2H, CHCH2), 0.84 (d, 3H, CH3).

[0081] 13 13C NMR (100 MHz, DMSO-d6) δ 169.41, 168.04, 135.17, 131.92, 123.68, 55.49, 52.67, 49.46, 48.18, 24.23, 22.31, 19.32.

[0082] HR-MS [M+H] + 317.1483 (calcd for C17H21N2O4+: 317.1496).

[0083] (10) Synthesis of 2,3-diaminopropionic acid derivative 3j

[0084]

[0085] Compound 2 (0.469 mmol, 0.1 g) was added to a 100 mL round-bottom flask, then α-naphthylamine (0.704 mmol, 100.8 mg) was added, 10 mL of toluene was added for dissolution, acetic acid (0.469 mmol, 27 μL) was added, and the mixture was heated to 65 °C and stirred for 12 h. After the reaction was completed, the solvent was removed by rotary evaporation, and column chromatography (DCM∶MeOH = 10∶1, 5‰ acetic acid) was carried out to obtain 2,3-diaminopropionic acid derivative 3j with different amino groups at the 3-position, which was a yellow solid. It had fluorescence at 254 nm and developed color with ninhydrin, and the yield was 65%.

[0086] 1 1H NMR (400 MHz, CHCl3-d) δ 7.86 (q, 2H, -naphthalene), 7.77–7.72 (m, 4H, -pht), 7.42 (t, 2H, -naphthalene), 7.35 (t, 1H, -naphthalene), 7.28 (s, 1H, -naphthalene), 6.70 (d, 1H, -naphthalene), 5.37 (t, 1H, CH), 4.17–4.05 (m, 2H, CH2).

[0087] (11) Synthesis of 2,3-diaminopropionic acid derivative 3k

[0088]

[0089] Compound 2 (0.469 mmol, 0.1 g) was added to a 100 mL round-bottom flask, then aniline (0.704 mmol, 64.2 μL) was added dropwise. 10 mL of toluene was added for dissolution, acetic acid (0.469 mmol, 27 μL) was added, and the mixture was heated to 65 °C and stirred for 12 h. After the reaction was completed, the solvent was removed by rotary evaporation, and column chromatography (DCM∶MeOH = 10∶1, 5‰ acetic acid) was carried out to obtain 2,3-diaminopropionic acid derivative 3k with different amino groups at the 3-position, which was a yellow solid. It had fluorescence at 254 nm, developed color with ninhydrin, and the yield was 69%.

[0090] 1 H NMR (400 MHz, CHCl3-d) δ 7.85–7.72 (m, 4H, -pht), 7.15 (t, 2H, -benzene), 6.73 (t, 1H, -benzene), 6.66 (d, 2H, -benzene), 5.16 (t, 1H, CH), 4.05–3.86 (m, 2H, CH2).

[0091] (12) Synthesis of 2,3-diaminopropionic acid derivative 3l

[0092]

[0093] Compound 2 (0.469 mmol, 0.1 g) was added to a 100 mL round-bottom flask, then o-bromoaniline (0.704 mmol, 121.1 mg) was added. 10 mL of toluene was added for dissolution, acetic acid (0.469 mmol, 27 μL) was added, and the mixture was heated to 65 °C and stirred for 12 h. After the reaction was completed, the solvent was removed by rotary evaporation, and column chromatography (PE∶EA = 7∶3, 5‰ acetic acid) was carried out to obtain 2,3-diaminopropionic acid derivative 3l with different amino groups at the 3-position, which was a brown oil. It had fluorescence at 254 nm, developed color with ninhydrin, and the yield was 82%.

[0094] (13) Synthesis of 2,3-diaminopropionic acid derivative 3m

[0095]

[0096] Compound 2 (0.469 mmol, 0.1 g) was added to a 100 mL round-bottom flask, followed by the addition of m-bromoaniline (0.704 mmol, 76.6 μL). 10 mL of toluene was added for dissolution, and acetic acid (0.469 mmol, 27 μL) was added. The mixture was heated to 65 °C and stirred for 12 h. After the reaction was completed, the solvent was removed by rotary evaporation, and column chromatography (PE∶EA = 7∶3, 5‰ acetic acid) was performed to obtain the 2,3-diaminopropionic acid derivative 3m with different amino groups at the 3-position, which was a yellow solid. It fluoresced at 254 nm and gave a color reaction with ninhydrin, with a yield of 65%.

[0097] (14) Synthesis of 2,3-diaminopropionic acid derivative 3n

[0098]

[0099] Compound 2 (0.469 mmol, 0.1 g) was added to a 100 mL round-bottom flask, followed by the addition of p-bromoaniline (0.704 mmol, 121.1 mg). 10 mL of toluene was added for dissolution, and acetic acid (0.469 mmol, 27 μL) was added. The mixture was heated to 65 °C and stirred for 12 h. After the reaction was completed, the solvent was removed by rotary evaporation, and column chromatography (PE∶EA = 7∶3, 5‰ acetic acid) was performed to obtain the 2,3-diaminopropionic acid derivative 3n with different amino groups at the 3-position, which was a brown oil. It fluoresced at 254 nm and gave a color reaction with ninhydrin, with a yield of 79%.

[0100] (15) Synthesis of 2,3-diaminopropionic acid derivative 3o

[0101]

[0102] Compound 2 (0.469 mmol, 0.1 g) was added to a 100 mL round-bottom flask, followed by the addition of o-iodoaniline (0.704 mmol, 154.1 mg). 10 mL of toluene was added for dissolution, and acetic acid (0.469 mmol, 27 μL) was added. The mixture was heated to 65 °C and stirred for 12 h. After the reaction was completed, the solvent was removed by rotary evaporation, and column chromatography (PE∶EA = 7∶3, 5‰ acetic acid) was performed to obtain the 2,3-diaminopropionic acid derivative 3o with different amino groups at the 3-position, which was a yellow oil. It fluoresced at 254 nm and gave a color reaction with ninhydrin, with a yield of 56.2%.

[0103] (16) Synthesis of 2,3-diaminopropionic acid derivative 3p

[0104]

[0105] Compound 2 (0.469 mmol, 0.1 g) was added to a 100 mL round-bottom flask, then p-trifluoromethylaniline (0.704 mmol, 87.5 μL) was added. 10 mL of toluene was added to dissolve, acetic acid (0.469 mmol, 27 μL) was added, and the mixture was heated to 65 °C and stirred for 12 h. After the reaction was completed, the solvent was removed by rotary evaporation, and column chromatography (PE∶EA = 5∶1, 5‰ acetic acid) was carried out to obtain 2,3-diaminopropionic acid derivative 3p with different amino groups at the 3-position, which was a yellow powder. It had fluorescence at 254 nm, developed color with ninhydrin, and the yield was 74%.

[0106] (17) Synthesis of 2,3-diaminopropionic acid derivative 3q

[0107]

[0108] Compound 2 (0.469 mmol, 0.1 g) was added to a 100 mL round-bottom flask, then 3,4,5-trimethoxyaniline (0.704 mmol, 129 mg) was added. 10 mL of toluene was added to dissolve, acetic acid (0.469 mmol, 27 μL) was added, and the mixture was heated to 65 °C and stirred for 12 h. After the reaction was completed, the solvent was removed by rotary evaporation, and column chromatography (PE∶EA = 7∶3, 5‰ acetic acid) was carried out to obtain 2,3-diaminopropionic acid derivative 3q with different amino groups at the 3-position, which was a brown oil. It had fluorescence at 254 nm, developed color with ninhydrin, and the yield was 81.1%.

[0109] (18) Synthesis of 2,3-diaminopropionic acid derivative 3r

[0110]

[0111] Compound 2 (0.469 mmol, 0.1 g) was added to a 100 mL round-bottom flask, then 3-methylaniline (0.704 mmol, 77 μL) was added. 10 mL of toluene was added to dissolve, acetic acid (0.469 mmol, 27 μL) was added, and the mixture was heated to 65 °C and stirred for 12 h. After the reaction was completed, the solvent was removed by rotary evaporation, and column chromatography (PE∶EA = 10∶1, 5‰ acetic acid) was carried out to obtain 2,3-diaminopropionic acid derivative 3r with different amino groups at the 3-position, which was a brown oil. It had fluorescence at 254 nm, developed color with ninhydrin, and the yield was 89.5%.

[0112] (19) Synthesis of 2,3-diaminopropionic acid derivative 3s

[0113]

[0114] Compound 2 (0.469 mmol, 0.1 g) was added to a 100 mL round-bottom flask, followed by o-ethylaniline (0.704 mmol, 86.8 μL). 10 mL of toluene was added for dissolution, and acetic acid (0.469 mmol, 27 μL) was added. The mixture was heated to 65 °C and stirred for 12 h. After the reaction was completed, the solvent was removed by rotary evaporation, and column chromatography (PE∶EA = 10∶1, 5‰ acetic acid) was performed to obtain the 2,3-diaminopropionic acid derivative 3s with different amino groups at the 3-position, which was a brown oil. It fluoresced at 254 nm and developed color with ninhydrin, with a yield of 96.1%.

[0115] (20) Synthesis of 2,3-diaminopropionic acid derivative 3t

[0116]

[0117] Compound 2 (0.469 mmol, 0.1 g) was added to a 100 mL round-bottom flask, followed by m-ethylaniline (0.704 mmol, 87.5 μL). 10 mL of toluene was added for dissolution, and acetic acid (0.469 mmol, 27 μL) was added. The mixture was heated to 65 °C and stirred for 12 h. After the reaction was completed, the solvent was removed by rotary evaporation, and column chromatography (PE∶EA = 10∶1, 5‰ acetic acid) was performed to obtain the 2,3-diaminopropionic acid derivative 3t with different amino groups at the 3-position, which was a yellow oil. It fluoresced at 254 nm and developed color with ninhydrin, with a yield of 64%.

[0118] (21) Synthesis of 2,3-diaminopropionic acid derivative 3u

[0119]

[0120] Compound 2 (0.469 mmol, 0.1 g) was added to a 100 mL round-bottom flask, followed by p-ethylaniline (0.704 mmol, 87.5 μL). 10 mL of toluene was added for dissolution, and acetic acid (0.469 mmol, 27 μL) was added. The mixture was heated to 65 °C and stirred for 12 h. After the reaction was completed, the solvent was removed by rotary evaporation, and column chromatography (PE∶EA = 10∶1, 5‰ acetic acid) was performed to obtain the 2,3-diaminopropionic acid derivative 3u with different amino groups at the 3-position, which was a brownish-yellow oil. It fluoresced at 254 nm and developed color with ninhydrin, with a yield of 86.5%.

[0121] (22) Synthesis of 2,3-diaminopropionic acid derivative 3v

[0122]

[0123] Compound 2 (0.469 mmol, 0.1 g) was added to a 100 mL round-bottom flask, then N-methyl-1-naphthylmethylamine (0.704 mmol, 115 μL) was added. 10 mL of toluene was added for dissolution, acetic acid (0.469 mmol, 27 μL) was added, and the mixture was heated to 65 °C and stirred for 12 h. After the reaction was completed, the solvent was removed by rotary evaporation, and column chromatography (DCM∶MeOH = 20∶1, 5‰ acetic acid) was performed to obtain the 2,3-diaminopropionic acid derivative 3v with different amino groups at the 3-position, which was a yellow powder. It had fluorescence at 254 nm, developed color with ninhydrin, and the yield was 66.2%.

[0124] (23) Synthesis of 2,3-diaminopropionic acid derivative 3w

[0125]

[0126] Compound 2 (0.469 mmol, 0.1 g) was added to a 100 mL round-bottom flask, then dibenzylamine (0.704 mmol, 135.4 μL) was added. 10 mL of toluene was added for dissolution, acetic acid (0.469 mmol, 27 μL) was added, and the mixture was heated to 65 °C and stirred for 12 h. After the reaction was completed, the solvent was removed by rotary evaporation, and column chromatography (PE∶EA = 5∶1, 5‰ acetic acid) was performed to obtain the 2,3-diaminopropionic acid derivative 3w with different amino groups at the 3-position, which was a yellow oil. It had fluorescence at 254 nm, developed color with ninhydrin, and the yield was 69%.

[0127] Example 3 Influence of various conditions on the yield when compound 2 reacts with amines

[0128] In this experiment, pyrrolidine was used as the amine compound, and the Michael addition reaction conditions with compound 2 were optimized. The reaction solvent, types of catalysts, reaction temperature, etc. were investigated respectively.

[0129] 1. Influence of reaction solvent on the yield

[0130] The amount of compound 2 used was 0.469 mmol. Using acetic acid as the catalyst, the molar ratio of reactants was compound 2∶pyrrolidine∶acetic acid = 1∶1.5∶1. The reaction was heated to 65 °C for 12 h, and six solvents, namely dichloromethane, toluene, acetonitrile, DMF, water, and methanol, were investigated respectively.

[0131] Table 1 Influence of reaction solvent on the yield

[0132]

[0133]

[0134] As can be seen from Table 1, the yield was the highest when the reaction solvent was toluene. Therefore, toluene was selected as the optimal reaction solvent.

[0135] When methanol was used as the solvent, a large amount of by-products appeared. It was speculated from the analysis of NMR data that it might be the salt obtained by the acid-base reaction of compound 2 with amines. When other solvents were used for the reaction, by-products also appeared, but in smaller amounts.

[0136] 2. Influence of different catalysts on the yield

[0137] The amount of compound 2 used was 0.469 mmol. Using toluene as the reaction solvent, the molar ratio of the reactants was compound 2∶pyrrolidine∶catalyst = 1∶1.5∶1. The reaction was heated to 65 °C for 12 h, and the effects of trifluoroacetic acid, p-toluic acid, phosphoric acid, hydrochloric acid, propionic acid, and acetic acid on the yield were investigated respectively.

[0138] Table 2 Influence of catalysts on the yield

[0139] Number Acid Yield (%) 1 Trifluoroacetic acid 23 2 p-Toluic acid 60 3 Acetic acid 79 4 Phosphoric acid 23 5 Propionic acid 74.6 6 Hydrochloric acid 34 7 Triethylamine 44.4 8 Triethylamine and acetic acid 63 9 Without catalyst 15

[0140] It can be seen from Table 2 that the yield was the highest when acetic acid was used as the catalyst. Therefore, acetic acid was selected as the best catalyst. (Note: In No. 2, the molar ratio of compound 2∶triethylamine∶acetic acid was 1∶1∶1)

[0141] 3. Influence of reaction temperature on the yield

[0142] The amount of compound 2 used was 0.469 mmol. Using toluene as the reaction solvent, the molar ratio of the reactants was compound 2∶pyrrolidine∶acetic acid = 1∶1.5∶1. The reaction was heated for 12 h, and the influence of the reaction yield at different temperatures was investigated.

[0143] Table 3 Influence of reaction temperature on the yield

[0144]

[0145]

[0146] It can be seen from Table 3 that as the temperature increased, the yield gradually increased. When the temperature reached 65 °C, the yield reached the highest. Therefore, we selected 65 °C as the best reaction temperature.

[0147] 4. Influence of reaction time on the yield

[0148] The amount of compound 2 used was 0.469 mmol. Using toluene as the reaction solvent, the molar ratio of the reactants was compound 2∶pyrrolidine∶acetic acid = 1∶1.5∶1. The reaction was heated to 65 °C, and the influence of different reaction times on the reaction yield was investigated.

[0149] Table 4 Influence of reaction time on the yield

[0150] Number Time (h) Yield (%) 1 1 41.8 2 2 44.7 3 4 46.3 4 6 46 5 8 62 6 10 76 7 12 79 8 24 42

[0151] It can be seen from Table 4 that the yield is the highest when the reaction proceeds for 12 h. Continuing to extend the reaction time, the yield does not increase but decreases. Therefore, 12 h is selected as the optimal reaction time.

[0152] 5. Influence of the feeding ratio of Compound 2 to pyrrolidine on the yield

[0153] The amount of Compound 2 used was 0.469 mmol. Using toluene as the reaction solvent, the molar ratio of the reactants was Compound 2∶acetic acid = 1∶1. The reaction was heated to 65 °C for 12 h, and the influence of different molar ratios of the reactants on the yield was investigated.

[0154] Table 5 Influence of the feeding ratio on the yield

[0155]

[0156]

[0157] It can be seen from Table 5 that the yield is the highest when the molar ratio of Compound 2 to pyrrolidine is 1:1.5.

[0158] 6. Influence of the amount of acetic acid used on the yield

[0159] The amount of Compound 2 used was 0.469 mmol. Using toluene as the reaction solvent, the molar ratio of the reactants was Compound 2∶pyrrolidine = 1∶1.5. The reaction was heated to 65 °C for 12 h, and the influence of the amount of acetic acid used on the yield was investigated.

[0160] Table 6 Influence of the amount of acetic acid used on the yield

[0161] Number Amount of acid (%) Yield (%) 1 20 33.7 2 75 58 3 100 79 4 200 72

[0162] It can be seen from Table 6 that the yield is the highest when the molar ratio of acetic acid to Compound 2 in the feed is 1. Therefore, the molar amount of acetic acid to the molar amount of Compound 2 of 1:1 is selected as the optimal reaction condition.

[0163] The preparation method of 2,3-diaminopropionic acid derivatives with different amino groups at the 3-position provided by the present invention involves performing a one-step reaction on serine to introduce the group pht (phthaloyl) group, eliminating the hydroxyl group to obtain a double bond, and then performing a Michael addition reaction with various aliphatic amines and aromatic amines to obtain a batch of 2,3-diaminopropionic acid derivatives. The synthesis method provided by the present invention not only has simple steps but also has a high reaction yield. When performing the Michael addition in the second step of the synthesis, the highest yield reaches 96.1%. At the same time, the raw materials involved in the present invention are easily available, the reaction conditions are mild, no dangerous operations are required, and no extreme conditions such as high temperature and high pressure are involved, opening up a new path for large-scale production in the later stage.

[0164] References:

[0165] 1. Perez, M., Pleixats, R, FeCl3-catalyzed conjugate addition of secondary amines, imidazole and pyrazole to methyl 2-acetamidoacrylate. Preparation of β-dialkylamino-α-alanine and β-(N-heteroaryi)-α-alanine derivatives, Tetrahedron, 1995, 51, 8355-8363。

[0166] 2. Abe, N, Fujisaki, F., Sumotom K., Synthesis of β-(sec-Amino)alanines, Chem. Pharm. Bull., 1998, 46, 142-144. 3. Belokon, Y.N., Sagyan, A.S., Djamgaryan, S.M., Bakhmutov, V.I, Belikov, V.M., Asymmetric synthesis of β-subsitituted α-amono acids via a chiral NiII complex of dehydroalanine. Tetrahedron, 1988, 44, 5507-5514。

[0167] 4. Sagiyan, A.S., Avetisyan, A.E., Djamgaryan, S.M, Djilavyan, L.R, Gyulumyan, E.A, Grigoryan, S.K., Kuzmina, N.A., Orlova, S.A., Ikonnikov. N.S., Larichev. V.S., Tararov. V.I., Belokon, Y.N., Asymmetric Synthesis of β-N-Substituted α,β-Diamino Acids via a Chiral Ni(II) Complex with a Dehydroalanine Derivative, Russ.Chem.Bull., 1997, 46, 483-496。

[0168] 5、Navo, C.D., Mazo, N.Oroz, P, Gutiérrez, M.I., Marin, J.Asenjo, J., Avenoza, A., Busto, J.H., Corzana, F., Zurbanom M.M., Jimenez, G., Peregrina, J.M., Synthesis of nβ-substituted α,β-diamino acids via stereoselective N-michael additions to achiral bicyclic dehydroalanine. The Journal of Organic Chemistry, 2020, 85, 3134-3145。

[0169] 6、Schneider, J.P., Kretsinger, J.K., Design and Application of Basic Amino Acids Displaying Enhanced Hydrophobicity, J.Am Chem.Soc., 2003, 125, 7907-7913。

Claims

1. A method for preparing 2,3-diaminopropionic acid derivatives with different amino groups at the 3-position, characterized in that: Using L-serine as a raw material, reacting with phthalic anhydride under the catalysis of triethylamine to obtain compound 2, and then performing a Michael addition reaction with amines to obtain 2,3-diaminopropionic acid derivatives with different amino groups at the 3-position; The preparation method comprises the following steps: a. Dissolve L-serine and phthalic anhydride in toluene, add triethylamine, and reflux for 2 - 6 h; after the reaction is completed, remove the solvent from the reactants, dissolve in dichloromethane, first remove the unreacted L-serine completely, and then after extraction, combining the organic phases, drying, and concentration, perform column chromatography to obtain compound 2; b. Dissolve compound 2 and amines in a solvent, add a catalyst, heat to 25 - 105 °C and stir for 1 - 24 h, after the reaction is completed, concentrate the reaction solution, and perform column chromatography to obtain 2,3-diaminopropionic acid derivatives with different amino groups at the 3-position; The amine is any one of C1-C4 alkylamines, wherein R1 to R4 are independently -H, halogen, -CF3, -OCH3 or C1-C4 alkyl; The reaction formula of the preparation method is as follows; The catalyst described in step b is any one of p-toluic acid, propionic acid, or acetic acid; the solvent described in step b is toluene or acetonitrile.

2. The method for preparing 2,3-diaminopropionic acid derivatives with different amino groups at the 3-position according to claim 1, characterized in that: The molar ratio of L-serine, phthalic anhydride, and triethylamine described in step a is 1:1:0.

11.

3. The method for preparing 2,3-diaminopropionic acid derivatives with different amino groups at the 3-position according to claim 1, characterized in that: The eluent for the column chromatography described in step a is a mixed solvent of petroleum ether and ethyl acetate, and their volume ratio is 5 - 10∶1 - 3; 5‰ of acetic acid based on the total volume of the eluent is also added to the eluent.

4. The method for preparing 2,3-diaminopropionic acid derivatives with different amino groups at the 3-position according to claim 1, characterized in that: The method for removing the unreacted L-serine completely described in step a is to wash the reactants dissolved in dichloromethane with 1 M hydrochloric acid aqueous solution 1 - 3 times.

5. The method for preparing 2,3-diaminopropionic acid derivatives with different amino groups at the 3-position according to claim 1, characterized in that: The molar ratio of compound 2, amines, and the catalyst described in step b is 1∶0.5 - 2∶0.2 - 2.

6. The method for preparing 2,3-diaminopropionic acid derivatives with different amino groups at the 3-position according to claim 1, characterized in that: The eluent for the column chromatography described in step b is a mixed solvent of dichloromethane and methanol, and their volume ratio is 10 - 20∶1, 5‰ of acetic acid based on the total volume of the eluent is also added to the eluent; or it is a mixed solvent of petroleum ether and ethyl acetate, and their volume ratio is 5 - 10∶1 - 3, 5‰ of acetic acid based on the total volume of the eluent is also added to the eluent.

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