A method for synthesizing azido amino acid derivatives

Abstract

The application relates to a synthesis method of an azido amino acid derivative, which comprises the following steps: step S1, reacting a compound shown in formula (II) with an amino protecting agent to generate a compound shown in formula (III); step S2, generating a compound shown in formula (I) (i.e. the azido amino acid derivative) by reacting the compound shown in formula (III) with an azido source in the presence of a catalyst and a solvent under the action of infrared radiation; in formula (I), the R1 is -CH2-N3; in formula (I) and formula (III), the R2 is an amino protecting group; in formula (II) and formula (III), the R3 is -CH2-OH. The synthesis method takes a 2-aminohydroxymethyl phenylpropionic acid derivative as a starting material, first protects the amino group, and then converts the hydroxyl group into an azido group under the action of infrared radiation and a catalyst, so that the yield is high, and the operation is simple. Further, the use of a strong toxic azido source is avoided, the safety is higher, and the method is more suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of organic compound synthesis technology, and specifically relates to a method for synthesizing azide amino acid derivatives. Background Technology

[0002] Non-natural amino acids, as a component of amino acids, have been widely used in the research of proteins, nucleosides, and nucleic acids. Incorporating non-natural amino acids into protein sequences to design and synthesize novel proteins is of great significance for studying the folding and function of natural proteins. To date, more than 30 non-natural amino acids have been artificially inserted into naturally synthesized proteins. Furthermore, the presence of non-natural amino acids can limit the conformational flexibility of peptides, provide DNA or ribonucleic acid molecules with stable secondary structures, enhance the stability of peptides to enzymes, and improve pharmacokinetics and biological activity. Therefore, the efficient synthesis of non-natural amino acids has become an important research topic in the fields of chemistry and biochemistry.

[0003] The attachment of azide groups to the amino acid molecule structure significantly influences the properties and functions of amino acids. First, the presence of azides enables amino acids to form polypeptide chains, linking amino acid molecules together via peptide bonds to constitute proteins. Second, azides also participate in regulating the acid-base and hydrophilic properties of amino acids, affecting their solubility and interactions. However, NaN3 is a commonly used azide source; however, using NaN3 as an azide source is highly explosive, prone to explosion from friction, collision, and vibration, and also exhibits strong toxicity, resulting in poor safety. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to provide a method for synthesizing azide amino acid derivatives with high safety, which is simple to operate, has a high yield, and is suitable for industrial production, in order to overcome the shortcomings of the prior art.

[0005] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0006] A method for synthesizing an azide amino acid derivative, wherein the structural formula of the azide amino acid derivative is shown in formula (I).

[0007]

[0008] The synthesis method includes the following steps:

[0009] Step S1: React the compound shown in formula (II) with an amino protecting agent to generate the compound shown in formula (III);

[0010] Step S2: The compound shown in formula (III) is reacted with an azide source in the presence of a catalyst and a solvent under infrared radiation to generate the compound shown in formula (I);

[0011] The structural formula of the compound shown in formula (II) is:

[0012] The structural formula of the compound shown in formula (III) is:

[0013] In formula (I), R1 is -CH2-N3; in formulas (I) and (III), R2 is an amino protecting group; in formulas (II) and (III), R3 is -CH2-OH.

[0014] In some embodiments, in formula (I), R1 is the para, meta, or ortho position of the CH2 group on the benzene ring; in formulas (II) and (III), R3 is the para, meta, or ortho position of the CH2 group on the benzene ring.

[0015] In some specific embodiments, the compound represented by formula (I) is as shown in the following compounds:

[0016]

[0017] In some embodiments, in step S2, the power of the infrared radiation is 200-350W and the radiation temperature is 10-40℃.

[0018] Furthermore, the power of the infrared radiation is 250–300W.

[0019] In some specific embodiments, in step S2, the infrared radiation time is 4 to 8 hours.

[0020] In some specific embodiments, in step S2, the azide source is one or a combination of several of diphenylphosphine azide (DPPA) and trimethylsilane azide. This avoids the use of highly toxic NaN3 azide sources, preventing explosions and ensuring higher safety.

[0021] In some specific embodiments, in step S2, the solvent is one or a combination of several of acetone, n-hexane, toluene, and dimethyl sulfoxide (DMSO); the catalyst is one or a combination of several of 1,5-diazabicyclo[4.3.0]-5-nonene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and tetramethylguanidine (TMG).

[0022] Preferably, in step S2, the solvent is a mixture of acetone and n-hexane. This avoids the use of toxic solvents such as toluene and helps to improve the product yield.

[0023] Furthermore, the volume ratio of acetone to n-hexane is 1:0.8 to 1.2.

[0024] Advantageously, the azide source is diphenylphosphine azide, the solvent is a mixture of acetone and n-hexane, and the reaction is carried out under infrared radiation, which can greatly promote the reaction, shorten the reaction time, and increase the product yield. At the same time, the experimental operation is simple, the post-processing is convenient, no other auxiliary solvents need to be added, and the cost is reduced.

[0025] In some specific embodiments, in step S2, the reaction is carried out under an inert gas atmosphere, such as nitrogen.

[0026] In some specific embodiments, the molar ratio of the compound represented by formula (III) to the azide source is 1:1 to 1.5; the molar ratio of the compound represented by formula (III) to the catalyst is 1:0.8 to 1.2.

[0027] In some specific embodiments, step S2 is specifically implemented as follows: under inert gas conditions, the compound shown in formula (III) is dissolved in a solvent, and then under ice bath conditions, an azide source and a catalyst are added to the system. Then, under infrared radiation conditions, the reaction is carried out at 10–40 °C. After the reaction is completed, the reaction is quenched.

[0028] In some specific embodiments, the synthesis method further includes a post-treatment step of the reaction solution after the quenching reaction is completed, the post-treatment including drying, solvent drying by rotary evaporation, and column chromatography purification.

[0029] In some embodiments, R2 is Boc or Fmoc; the amino protecting agent is selected from di-tert-butyl dicarbonate or fluorenemethyloxycarbonyl succinimide (Fmoc-OSu).

[0030] In some specific embodiments, in step S1, the reaction is carried out in the presence of a solvent, which is a mixture of an organic solvent and water, and the organic solvent is one or a combination of several of dioxane, tetrahydrofuran, and N,N-dimethylformamide.

[0031] In some specific embodiments, in step S1, the reaction is carried out at 15–40°C in the presence of a base, wherein the base is one or a combination of sodium carbonate, sodium hydroxide, sodium bicarbonate, potassium carbonate, and potassium tert-butoxide.

[0032] In some specific embodiments, when the amino protecting agent is di-tert-butyl dicarbonate, step S1 is specifically implemented as follows: under ice bath conditions, the compound shown in formula (II), solvent and base are added to the reactor, and then the amino protecting agent and base are added to the reactor. The reaction is carried out at 15-40°C for 6-10 hours. The solvent is evaporated, diluted with ethyl acetate in an ice bath, acidified to pH 2-3, extracted, washed with water and combined with organic phases, dried and evaporated to obtain the compound shown in formula (III).

[0033] In some specific embodiments, when the amino protecting agent is fluorenemethyloxycarbonyl succinimide, step S1 is specifically implemented as follows: under ice bath conditions, the amino protecting agent is dissolved in a solvent and then added to a reactor containing the compound shown in formula (II), a solvent and a base, and reacted at 15-40°C for 6-10 hours. After extraction, the pH is adjusted to 1-3, extracted, washed with weak acid water, dried, concentrated and recrystallized to obtain the compound shown in formula (III).

[0034] Due to the application of the above technical solution, the present invention has the following advantages compared with the prior art:

[0035] The synthesis method of this invention uses a 2-aminohydroxymethylphenylpropionic acid derivative as a starting material. First, it protects the derivative with an amino group, and then, under the action of infrared radiation and a catalyst, converts the hydroxyl group into an azide group. This method offers high yield and is simple to operate. Furthermore, it avoids the use of highly toxic azide sources, resulting in higher safety and making it more suitable for industrial production. Attached Figure Description

[0036] Figure 1 The NMR spectrum of 3-(4-(azidomethyl)phenyl)-2-((tert-butoxycarbonyl)amino)propionic acid from Example 1 is shown. Detailed Implementation

[0037] The technical solutions of the present invention will be described in detail below with reference to specific embodiments, so that those skilled in the art can better understand and implement the technical solutions of the present invention, but the present invention is not limited to the scope of the examples described.

[0038] The raw materials may be obtained commercially, or prepared by methods known in the art, or prepared according to the methods described herein.

[0039] The structure of the compound was determined by nuclear magnetic resonance (¹H-NMR). NMR determination was performed using an ACF-400BRUKER NMR spectrometer. The solvents used were deuterated chloroform (CDCl₃), deuterated dimethyl sulfoxide (DMSO-D₆), or heavy water (D₂O), with TMS as an internal standard. Column chromatography was performed using 200-300 mesh silica gel (produced by Qingdao Ocean Chemical Plant).

[0040] Example 1

[0041] This embodiment provides the synthesis of 3-(4-(azidomethyl)phenyl)-2-((tert-butoxycarbonyl)amino)propionic acid.

[0042]

[0043] The synthesis method includes the following steps:

[0044] Step S1: Under ice bath conditions, 2-amino-3-(4-(hydroxymethyl)phenyl)propionic acid (1.95 g, 10 mmol), dioxane / H₂O (v / v = 2:1, 30 mL), and NaOH (1 M, 10 mmol) were added to a 150 mL round-bottom flask. (Boc)₂O (Boc anhydride) (3.27 g, 15 mmol) and NaHCO₃ (10 mmol) were added to the reaction mixture, and the mixture was reacted overnight at room temperature for 8 h. The solvent was evaporated to dryness, and the residue was diluted with ethyl acetate (40 mL) in an ice bath and acidified to pH 2-3 with 1.0 M HCl. The aqueous phase was extracted with EtOAc (2 × 20 mL), washed several times with water, and the organic phases were combined, dried over anhydrous Na₂SO₄, and evaporated to dryness to give 2-((tert-butoxycarbonyl)amino)-3-(4-(hydroxymethyl)phenyl)propionic acid (2.9 g, 98.1%).

[0045] Step S2: Under N2 conditions, 2-((tert-butoxycarbonyl)amino)-3-(4-(hydroxymethyl)phenyl)propionic acid (2.95 g, 10 mmol) was dissolved in a 10 mL mixture of acetone and n-hexane (1:1). Then, under ice bath conditions, diphenylphosphohydrazine (3.0 g, 11 mmol) and DBN (1.3 g, 10.5 mmol) were rapidly added to the mixture, followed by infrared irradiation (220 V, 275 W) using an infrared spectrometer, and the reaction was stirred at room temperature for 6 h. After the reaction was complete, the reaction was quenched sequentially with water (10 mL) and then with 5% HCl aqueous solution (10 mL). The reaction mixture was extracted with EtOAc (2 × 10 mL). The mixture was dried over anhydrous MgSO4 and the solvent was evaporated. Purified by column chromatography and then eluted with hexane / EtOAc (V / V = 20 / 1) to give 3-(4-(azidomethyl)phenyl)-2-((tert-butoxycarbonyl)amino)propionic acid (3.17 g, 99.1%).

[0046] MRI results:

[0047] 1 H NMR (400MHz, CDCl3) δ8.03(s,1H),7.30(dt,2H),6.96(dt,2H),6.67(d,1H),4.24(m,3H),3.05(m,2H),1.41(s,9H).

[0048] Example 2

[0049] This embodiment provides the synthesis of 2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(4-(azidomethyl)phenyl)propionic acid.

[0050]

[0051] The synthesis method includes the following steps:

[0052] Step S1: At 0°C, Fmoc-OSu (1.35 g, 4 mmol) was dissolved in tetrahydrofuran (10 mL) solution and added to 2-amino-3-(4-(hydroxymethyl)phenyl)propionic acid (0.78 g, 4 mmol) in 12 mL of 10% Na2CO3 solution. The mixture was stirred overnight at room temperature for 7 h. After the reaction was completed, the mixture was extracted with PE, then the pH was adjusted to 2, and extracted with ethyl acetate (20 mL × 3). The mixture was washed with acetic acid, dried, concentrated, and recrystallized to obtain 2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(4-(hydroxymethyl)phenyl)propionic acid (1.6 g, 96.5%).

[0053] Step S2: Under N2 conditions, 2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(4-(hydroxymethyl)phenyl)propionic acid (4.17 g, 10 mmol) was dissolved in a 10 mL mixture of acetone and n-hexane (1:1). Then, under ice bath conditions, diphenylphosphohydride (3.0 g, 11 mmol) and DBN (1.3 g, 10.5 mmol) were rapidly added to the mixture, followed by infrared irradiation (220 V, 275 W) using an infrared spectrometer, and the reaction was stirred at room temperature for 7 h. After the reaction was complete, the reaction was quenched sequentially with water (10 mL) and then with 5% HCl aqueous solution (10 mL). The reaction mixture was extracted with EtOAc (2 × 10 mL). The mixture was dried over anhydrous MgSO4 and the solvent was evaporated. Purified by column chromatography and then eluted with hexane / EtOAc (V / V = 20 / 1) to give 2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(4-(azidomethyl)phenyl)propionic acid (4.39 g, 99.3%).

[0054] MRI results:

[0055] 1 H NMR (400MHz, DMSO) δ10.11(s,1H),7.65(m,8H),7.30(dt,2H),6.91(dt,2H),6.18(d,1H),5.60(m,1H),4.36(d,2H),4.25(m,3H),3.06(dq,2H).

[0056] Example 3

[0057] This embodiment provides the synthesis of 3-(3-(azidomethyl)phenyl)-2-((tert-butoxycarbonyl)amino)propionic acid.

[0058]

[0059] In this example, 10 mmol of 2-amino-3-(3-(hydroxymethyl)phenyl)propionic acid was used instead of 2-amino-3-(4-(hydroxymethyl)phenyl)propionic acid, and the rest was basically the same as in Example 1. The final overall yield of 3-(3-(azidomethyl)phenyl)-2-((tert-butoxycarbonyl)amino)propionic acid was 97.1%.

[0060] 1 H NMR(400MHz, CDCl3)δ8.24(s,1H),7.33(dp,1H),7.23(t,1H),7.13(hept,1H),7. 01(dq,1H),6.67(d,1H),4.21(m,3H),3.08(ddt,1H),3.01(ddt,1H),1.41(s,9H).

[0061] Example 4

[0062] This embodiment provides the synthesis of 3-(2-(azidomethyl)phenyl)-2-((tert-butoxycarbonyl)amino)propionic acid.

[0063]

[0064] In this example, 10 mmol of 2-amino-3-(2-(hydroxymethyl)phenyl)propionic acid was used instead of 2-amino-3-(4-(hydroxymethyl)phenyl)propionic acid, and the rest was basically the same as in Example 1. The final total yield of 3-(2-(azidomethyl)phenyl)-2-((tert-butoxycarbonyl)amino)propionic acid was 96.9%.

[0065] 1 H NMR(400MHz, CDCl3)δ8.11(s,1H),7.30(ddt,1H),7.23(td,1H),7.16(td,1H),7 .00(dq,1H),6.90(d,1H),4.33(m,2H),4.24(dt,1H),3.09(m,2H),1.45(s,9H).

[0066] Example 5

[0067] This embodiment provides the synthesis of 2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(3-(azidomethyl)phenyl)propionic acid.

[0068]

[0069] In this example, 10 mmol of 2-amino-3-(3-(hydroxymethyl)phenyl)propionic acid was used instead of 2-amino-3-(4-(hydroxymethyl)phenyl)propionic acid, and the rest was basically the same as in Example 2. The final overall yield of 2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(3-(azidomethyl)phenyl)propionic acid was 97.3%.

[0070] 1 H NMR(400MHz,DMSO)δ9.93(s,1H),7.81(dd,2H),7.70(m,2H),7.60(td,2H),7.52(td,2H),7.33(m,1H),7.24(t,1 H),7.13(hept,1H),6.99(m,1H),6.38(d,1H),5.41(m,1H),4.36(d,2H),4.23(m,1H),4.18(m,2H),3.05(m,2H).

[0071] Example 6

[0072] This embodiment provides the synthesis of 2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(2-(azidomethyl)phenyl)propionic acid.

[0073]

[0074] In this embodiment, 10 mmol of 2-amino-3-(2-(hydroxymethyl)phenyl)propionic acid was used instead of 2-amino-3-(4-(hydroxymethyl)phenyl)propionic acid, and the rest was basically the same as in Example 2. The final overall yield of 2-((((9H-fluorene-9-yl)methoxy)carbonyl)amino)-3-(2-(azidomethyl)phenyl)propionic acid was 96.6%.

[0075] 1 H NMR(400MHz,DMSO)δ9.82(s,1H),7.81(dd,2H),7.70(m,2H),7.60(td,2H),7.52(td,2H),7.30(ddt,1 H),7.22(dtd,2H),6.95(ddt,1H),6.52(d,1H),5.61(m,1H),4.35(m,4H),4.24(dt,1H),3.07(m,2H).

[0076] Example 7

[0077] This embodiment provides the synthesis of 3-(4-(azidomethyl)phenyl)-2-((tert-butoxycarbonyl)amino)propionic acid. The synthesis method is basically the same as in Example 1, except that 10 mL of toluene is used instead of the mixed solution of acetone and n-hexane.

[0078] 2-((tert-butoxycarbonyl)amino)-3-(4-(hydroxymethyl)phenyl)propionic acid (2.95 g, 10 mmol) was dissolved in toluene solution (10 mL) under N2 conditions. Then, diphenylphosphohydrin (3.0 g, 11 mmol) and DBN (1.3 g, 10.5 mmol) were rapidly added to the mixture under ice bath conditions, followed by infrared irradiation (220 V, 275 W) with stirring at room temperature for 6 h. After the reaction was complete, the reaction was quenched sequentially with water (10 mL) and then with 5% HCl aqueous solution (10 mL). The reaction mixture was extracted with EtOAc (2 × 10 mL). The solution was dried over anhydrous MgSO4 and the solvent was evaporated. Purification was achieved by column chromatography, followed by elution with hexane / EtOAc (V / V = 20 / 1) to give 3-(4-(azidomethyl)phenyl)-2-((tert-butoxycarbonyl)amino)propionic acid (2.7 g, 85%).

[0079] Example 8

[0080] This embodiment provides the synthesis of 3-(4-(azidomethyl)phenyl)-2-((tert-butoxycarbonyl)amino)propionic acid. The synthesis method is basically the same as in Example 1, except that DBU is used instead of DBN.

[0081] Under N2 conditions, 2-((tert-butoxycarbonyl)amino)-3-(4-(hydroxymethyl)phenyl)propionic acid (2.95 g, 10 mmol) was dissolved in a 10 mL mixture of acetone and n-hexane (1:1). Then, under ice bath conditions, diphenylphosphohydrazine (3.0 g, 11 mmol) and DBU (1.6 g, 10.5 mmol) were rapidly added to the mixture, followed by infrared irradiation (220 V, 275 W) using an infrared spectrometer, and the mixture was stirred at room temperature for 6 h. After the reaction was complete, the reaction was quenched sequentially with 10 mL of water and 10 mL of 5% HCl aqueous solution. The reaction mixture was extracted with EtOAc (2 × 10 mL). The solution was dried over anhydrous MgSO4 and the solvent was evaporated. Purified by column chromatography and then eluted with hexane / EtOAc (V / V = 20 / 1) to give 3-(4-(azidomethyl)phenyl)-2-((tert-butoxycarbonyl)amino)propionic acid (2.85 g, 89%).

[0082] Comparative Example 1

[0083] This comparative example provides the synthesis of 3-(4-(azidomethyl)phenyl)-2-((tert-butoxycarbonyl)amino)propionic acid. The synthesis method is basically the same as in Example 1, except that infrared radiation is not performed using an infrared radiation meter in step S2.

[0084] Under N2 conditions, 2-((tert-butoxycarbonyl)amino)-3-(4-(hydroxymethyl)phenyl)propionic acid (2.95 g, 10 mmol) was dissolved in a 10 mL mixture of acetone and n-hexane (1:1). Then, under ice bath conditions, diphenylphosphohydrazine (3.0 g, 11 mmol) and DBN (1.3 g, 10.5 mmol) were rapidly added to the mixture, and the mixture was stirred at room temperature for 6 h. After the reaction was complete, the reaction was quenched sequentially with water (10 mL) and then with 5% HCl aqueous solution (10 mL). The reaction mixture was extracted with EtOAc (2 × 10 mL). The solution was dried over anhydrous MgSO4 and the solvent was evaporated. Purification was performed by column chromatography, followed by elution with hexane / EtOAc (V / V = 20 / 1) to give 3-(4-(azidomethyl)phenyl)-2-((tert-butoxycarbonyl)amino)propionic acid (1.6 g, 50%).

[0085] The above embodiments are only for illustrating the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the content of the present invention and implement it accordingly. They should not be construed as limiting the scope of protection of the present invention. All equivalent changes or modifications made in accordance with the spirit and essence of the present invention should be covered within the scope of protection of the present invention.

[0086] The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

Claims

1. A method for synthesizing an azide amino acid derivative, wherein the structural formula of the azide amino acid derivative is shown in formula (I), ； Its features are, The synthesis method includes the following steps: Step S1: React the compound shown in formula (II) with an amino protecting agent to generate the compound shown in formula (III); Step S2: The compound shown in formula (III) is reacted with an azide source in the presence of a catalyst and a solvent under infrared radiation to generate the compound shown in formula (I); the azide source is diphenylphosphine azide; the solvent is a mixture of acetone and n-hexane; the catalyst is 1,5-diazabicyclo[4.3.0]-5-nonene; The structural formula of the compound shown in formula (II) is: ; The structural formula of the compound shown in formula (III) is: ; In formula (I), R1 is -CH2-N3; in formulas (I) and (III), R2 is Boc or Fmoc; in formulas (II) and (III), R3 is -CH2-OH.

2. The method for synthesizing azide amino acid derivatives according to claim 1, characterized in that: In step S2, the power of the infrared radiation is 200-350W, and the radiation temperature is 10-40℃.

3. The method for synthesizing azide amino acid derivatives according to claim 2, characterized in that: In step S2, the infrared radiation time is 4 to 8 hours.

4. The method for synthesizing azide amino acid derivatives according to claim 1, characterized in that: In step S2, the reaction is carried out under an inert gas atmosphere.

5. The method for synthesizing azide amino acid derivatives according to claim 1, characterized in that: The molar ratio of the compound shown in formula (III) to the azide source is 1:1 to 1.

5.

6. The method for synthesizing azide amino acid derivatives according to claim 1, characterized in that: The molar ratio of the compound shown in formula (III) to the catalyst is 1:0.8 to 1.

2.

7. The method for synthesizing the azide amino acid derivative according to any one of claims 1 to 6, characterized in that: The specific implementation of step S2 is as follows: under inert gas conditions, the compound shown in formula (III) is dissolved in a solvent, and then under ice bath conditions, an azide source and a catalyst are added to the system. Then, under infrared radiation conditions, the reaction is carried out at 10–40 °C. After the reaction is completed, the reaction is quenched.

8. The method for synthesizing azide amino acid derivatives according to claim 7, characterized in that: The synthesis method further includes a post-treatment step of the reaction solution after the quenching reaction is completed, which includes drying, solvent drying by rotary evaporation, and column chromatography purification.

9. The method for synthesizing azide amino acid derivatives according to claim 1, characterized in that: The amino protecting agent is selected from di-tert-butyl dicarbonate and fluorenemethyloxycarbonyl succinimide.

10. The method for synthesizing azide amino acid derivatives according to claim 1, characterized in that: In step S1, the reaction is carried out in the presence of a solvent, which is a mixture of an organic solvent and water, and the organic solvent is one or a combination of several of dioxane, tetrahydrofuran, and N,N-dimethylformamide.

11. The method for synthesizing azide amino acid derivatives according to claim 1, characterized in that: In step S1, the reaction is carried out at 15–40°C in the presence of a base.

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