Preparation method of Fmoc-L-Lys(ivDde)-OH

Abstract

The present invention provides a method for preparing Fmoc-L-Lys(ivDde)-OH, comprising the following steps: step S1, making N α The fluorenylmethoxycarbonyl-L-lysine radical compound undergoes esterification reaction with trialkylchlorosilane to generate N α ‑Fluorenylmethoxycarbonyl‑L‑lysine silane ester; Step S2, making the N α ‑Fluorenylmethoxycarbonyl‑L‑lysine silyl ester reacts with 2‑(1‑hydroxy‑3‑methylbutenyl)‑5,5‑dimethyl‑1,3‑cyclohexanedione to generate N α ‑Fluorenylmethoxycarbonyl‑N γ -[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl]-L-lysine silane ester; Step S3, making the N α ‑Fluorenylmethoxycarbonyl‑N γ ‑[1‑(4,4‑dimethyl‑2,6‑dioxocyclohexylidene)‑3‑methylbutyl]‑L‑lysine silyl ester undergoes a hydrolysis reaction to generate Fmoc‑L‑Lys(ivDde)‑OH. The preparation method of the present invention can effectively avoid the occurrence of side reactions, and the purification process of the target product is simple and easy.

Description

Technical Field

[0001] The invention belongs to the technical field of compound preparation, and more specifically, relates to a method for preparing Fmoc-L-Lys(ivDde)-OH. Background Art

[0002] L-Lysine (L-Lys) is one of the essential amino acids required by the human body, which can promote development, enhance immunity, and improve the function of central nervous tissue. However, its content in our cereal foods is very low and it is easily destroyed during processing. It is called the first limiting amino acid.

[0003] Protected L-lysine (L-Lys) is widely used in peptide synthesis, such as the synthesis of spider toxins and trypanosoma toxins. The two amino groups of amino acids are usually orthogonally protected, the α-amino group is protected by fluorenylmethyloxycarbonyl (fmoc), and the terminal amino group is generally protected by ivDde (2-(3-methylbutyryl)-5,5-dimethyl-1,3-cyclohexanedione) or Dde (2-acetyl-5,5-dimethyl-1,3-cyclohexanedione). This is because ivDde and Dde are easily removed in a 2% v / v hydrazine solution, but are stable in a pyridine solution or a trifluoroacetic acid solution, which is very suitable for use in the grafting and cyclization links in peptide synthesis.

[0004] About Fmoc-L-Lys(ivDde)-OH (i.e.: N α -Fluorenylmethoxycarbonyl-N γ There are few reports on the synthesis of 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl]-L-lysine. The main synthesis route is: using ethanol as solvent and raw material N α -Fluorenylmethoxycarbonyl-L-lysine and 2-(1-hydroxy-3-methylbutenyl)-5,5-dimethyl-1,3-cyclohexanedione were refluxed for 60 hours under the catalysis of trifluoroacetic acid to obtain the target product (Tetrahedron Letters, 1998, 39(12),: 1603-1606).

[0005] However, when the inventors repeated the preparation under the same conditions, they found that the raw material N α-Fluorenylmethoxycarbonyl-L-lysine (CAS No.: 105047-45-8) can easily eliminate the fluorenylmethoxycarbonyl group under this condition. In addition, both the α-amino group and the terminal amino group can react with 2-(1-hydroxy-3-methylbutenyl)-5,5-dimethyl-1,3-cyclohexanedione to produce an impurity that is difficult to remove. According to HPLC analysis and area normalization method, the proportion of this impurity is 10%~15%. Even after two crystallizations, the impurity is still around 1%, and the total yield after recrystallization is only around 40%, which significantly reduces the economy and efficiency of the process. In addition, N α -Fluorenylmethoxycarbonyl-L-lysine reacts directly with 2-(1-hydroxy-3-methylbutenyl)-5,5-dimethyl-1,3-cyclohexanedione, and may also produce a by-product whose carboxyl group is protected by 2-(1-hydroxy-3-methylbutenyl)-5,5-dimethyl-1,3-cyclohexanedione, which affects the product quality and yield. Summary of the invention

[0006] In view of this, the object of the present invention is to provide a method for preparing Fmoc-L-Lys(ivDde)-OH with less impurities, high yield and strong route feasibility.

[0007] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0008] The preparation method of Fmoc-L-Lys(ivDde)-OH according to an embodiment of the present invention comprises the following steps:

[0009] Step S1, make N α -Fluorenylmethoxycarbonyl-L-lysine radical compound undergoes esterification reaction with trialkylchlorosilane to generate N α -Fluorenylmethoxycarbonyl-L-lysine silyl ester, the N α -Fluorenylmethoxycarbonyl-L-lysine root compound is N α -Fluorenylmethoxycarbonyl-L-lysine and / or N α -Fmoc-L-lysine hydrochloride;

[0010] Step S2, making the N α -Fluorenylmethoxycarbonyl-L-lysine silyl ester reacts with 2-(1-hydroxy-3-methylbutenyl)-5,5-dimethyl-1,3-cyclohexanedione to generate N α -Fluorenylmethoxycarbonyl-N γ -[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl]-L-lysine silyl ester;

[0011] Step S3, making the N α -Fluorenylmethoxycarbonyl-N γ-[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl]-L-lysine silyl ester undergoes a hydrolysis reaction to generate Fmoc-L-Lys(ivDde)-OH.

[0012] In some embodiments of the present invention, the trialkylchlorosilane is any one or more of trimethylchlorosilane, triethylchlorosilane, and tert-butyldimethylchlorosilane.

[0013] Furthermore, the esterification reaction is carried out in an organic solvent under the action of an organic base, wherein the organic solvent is selected from any one or more of dichloromethane, tetrahydrofuran, 1,2-dichloroethane, and N,N-dimethylformamide, and the organic base is selected from any one or more of triethylamine, N,N-diisopropylethylamine, and pyridine.

[0014] Furthermore, the N α The molar ratio of -fluorenylmethoxycarbonyl-L-lysine root compound:trialkylchlorosilane:organic base is 1:(1.0-1.5):(1.0-2.5).

[0015] Furthermore, the reaction temperature of the esterification reaction is -5~40°C, and the reaction time is 2~8 h.

[0016] In some embodiments of the present invention, step S2 includes:

[0017] After the esterification reaction is completed, the 2-(1-hydroxy-3-methylbutenyl)-5,5-dimethyl-1,3-cyclohexanedione is added dropwise into the reaction system to cause the addition reaction.

[0018] Furthermore, the N α The molar ratio of -fluorenylmethoxycarbonyl-L-lysine root compound:2-(1-hydroxy-3-methylbutenyl)-5,5-dimethyl-1,3-cyclohexanedione is 1:(1.0-1.5).

[0019] Furthermore, the reaction temperature of the addition reaction is room temperature, and the reaction time is 2-10 hours.

[0020] In some embodiments of the present invention, the hydrolysis reaction comprises:

[0021] After the addition reaction is completed, ice water is added to quench the reaction, and an acid aqueous solution is added to cause the hydrolysis reaction. The acid aqueous solution includes any one or more of a hydrochloric acid aqueous solution, an acetic acid aqueous solution, and a sulfuric acid aqueous solution.

[0022] In some embodiments of the present invention, after the hydrolysis reaction is completed, the steps of liquid separation, drying, evaporating the solvent, and purifying the obtained crude product by column chromatography to obtain the Fmoc-L-Lys(ivDde)-OH are further included.

[0023] The above technical solution of the present invention has at least one of the following beneficial effects:

[0024] According to the preparation method of the present invention, N α -Fluorenylmethoxycarbonyl-L-lysine reacts directly with 2-(1-hydroxy-3-methylbutenyl)-5,5-dimethyl-1,3-cyclohexanedione, but firstly N α -Fluorenylmethoxycarbonyl-L-lysine reacts with trialkylchlorosilane to protect the carboxyl group to avoid side reactions and improve its solubility, and then reacts with 2-(1-hydroxy-3-methylbutenyl)-5,5-dimethyl-1,3-cyclohexanedione, and finally removes the silyl ether by hydrolysis to obtain the target product N α -Fluorenylmethoxycarbonyl-N γ -[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl]-L-lysine, according to the preparation method of the present invention, the occurrence of side reactions can be effectively avoided, and the purification treatment of the target product is simple and easy;

[0025] According to the preparation method of the embodiment of the present invention, a one-pot method can be adopted, which is not only simple to operate but also can effectively reduce the three wastes, has a high yield, and has a stronger feasibility of the route, and is suitable for industrial production. DETAILED DESCRIPTION

[0026] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution of the present invention will be clearly and completely described in combination with the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the described embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field belong to the scope of protection of the present invention.

[0027] The following first describes in detail the preparation method of Fmoc-L-Lys(ivDde)-OH according to an embodiment of the present invention.

[0028] The preparation method of Fmoc-L-Lys(ivDde)-OH according to an embodiment of the present invention comprises the following steps:

[0029] Step S1, make N α -Fluorenylmethoxycarbonyl-L-lysine radical compound undergoes esterification reaction with trialkylchlorosilane to generate N α -Fluorenylmethoxycarbonyl-L-lysine silyl ester, the N α-Fluorenylmethoxycarbonyl-L-lysine root compound is N α -Fmoc-L-Lysine (Fmoc-L-Lys-OH) and / or N α -Fmoc-L-Lysine hydrochloride (Fmoc-L-Lys-OH·HCl) (that is, as the starting material, either Fmoc-L-Lys-OH or Fmoc-L-Lys-OH·HCl may be used, or a mixture of both may be used).

[0030] That is, first, Fmoc-L-Lys-OH, Fmoc-L-Lys-OH·HCl, or a mixture thereof is reacted with trialkylchlorosilane to protect the carboxyl group and avoid the production of by-products (the carboxyl group in the by-product is protected by 2-(1-hydroxy-3-methylbutenyl)-5,5-dimethyl-1,3-cyclohexanedione), which can not only effectively improve the yield, but also make the purification of the final product simple and easy to operate, thereby significantly improving the economy and efficiency of the process; in addition, since the carboxyl group is adjacent to the α-amino group, the steric hindrance of the α-amino group is greatly improved by protecting the carboxyl group, thereby avoiding the subsequent reaction with 2-(1-hydroxy-3-methylbutenyl)-5,5-dimethyl-1,3-cyclohexanedione to produce impurities that are difficult to remove, thereby further improving the yield and simplifying the post-processing purification.

[0031] Specifically, the reaction process is shown in the following formula (1), where N α The structural formula of -fluorenylmethoxycarbonyl-L-lysine silane ester is shown as "I":

[0032] .

[0033] In some embodiments of the present invention, the trialkyl chlorosilane may be any one or more of trimethyl chlorosilane (TMS-Cl), triethyl chlorosilane (TES-Cl), tert-butyl dimethyl chlorosilane (TBS-Cl). Among them, trimethyl chlorosilane is cheap and easier to remove by simple hydrolysis reaction, which can effectively shorten the reaction time and improve the efficiency, so it is preferred.

[0034] Furthermore, the esterification reaction is carried out in an organic solvent under the action of an organic base. The presence of the base can promote the esterification reaction.

[0035] The organic solvent is selected from any one or more of dichloromethane, tetrahydrofuran, 1,2-dichloroethane, and N,N-dimethylformamide (DMF). Dichloromethane is preferred because it has a wide solubility range, low toxicity, is almost insoluble in water, and is easy to post-process.

[0036] The organic base is selected from any one or more of triethylamine, N,N-diisopropylethylamine (DIEA), and pyridine. Among them, DIEA has a large steric hindrance and is not easy to cause the removal of the Fmoc group, which reduces side reactions and is therefore preferred.

[0037] Furthermore, the N α The molar ratio of -fluorenylmethoxycarbonyl-L-lysine root compound: trialkylchlorosilane: organic base is 1: (1.0-1.5): (1.0-2.5). Preferably, when Fmoc-L-Lys-OH is used as a raw material, the molar ratio of Fmoc-L-Lys-OH: trialkylchlorosilane: organic base is 1: 1.1: 1.2; when Fmoc-L-Lys-OH·HCl is used as a raw material, the molar ratio of Fmoc-L-Lys-OH·HCl: trialkylchlorosilane: organic base is 1: 1.1: 2.2, which can fully ensure that the raw materials react completely. When a mixture of the two is used, the organic base therein can be appropriately selected between the above two ratios according to the mixing ratio of the two.

[0038] Furthermore, the reaction temperature of the esterification reaction is -5~40°C, and the reaction time is 2~8 h. The reaction temperature is preferably 0~5°C. At this temperature, the occurrence of the Fmoc removal side reaction can be effectively avoided and the operation is convenient. In addition, taking into account the reaction efficiency and yield, the reaction time is preferably 3 h.

[0039] Step S2, making the N α -Fluorenylmethoxycarbonyl-L-lysine silyl ester reacts with 2-(1-hydroxy-3-methylbutenyl)-5,5-dimethyl-1,3-cyclohexanedione (ivDde-OH) to generate N α -Fluorenylmethoxycarbonyl-N γ -[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl]-L-lysine silyl ester.

[0040] That is to say, after the carboxyl group is protected, the N α -Fluorenylmethoxycarbonyl-L-lysine silyl ester reacts with 2-(1-hydroxy-3-methylbutenyl)-5,5-dimethyl-1,3-cyclohexanedione to generate an unstable intermediate N α -Fluorenylmethoxycarbonyl-N γ -[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl]-L-lysine silyl ester.

[0041] Specifically, its chemical reaction formula is shown in the following formula (2): N α -Fluorenylmethoxycarbonyl-N γThe structural formula of -[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl]-L-lysine silane ester is shown as "II": .

[0042] In some embodiments of the present invention, step S2 includes:

[0043] After the esterification reaction is completed, the 2-(1-hydroxy-3-methylbutenyl)-5,5-dimethyl-1,3-cyclohexanedione is added dropwise into the reaction system to cause the addition reaction.

[0044] That is to say, there is no need to perform any treatment on the reaction system after the esterification reaction, and ivDde-OH can be directly added thereto to carry out the addition reaction, which is simple to operate and produces less waste.

[0045] Furthermore, N α The molar ratio of fluorenylmethoxycarbonyl-L-lysine root compound (Fmoc-L-Lys-OH and / or Fmoc-L-Lys-OH·HCl): 2-(1-hydroxy-3-methylbutenyl)-5,5-dimethyl-1,3-cyclohexanedione (ivDde-OH) is 1:(1.0-1.5). It should be noted that when a mixture of Fmoc-L-Lys-OH and Fmoc-L-Lys-OH·HCl is used, the N α Preferably, the molar ratio of Fmoc-L-Lys-OH (or Fmoc-L-Lys-OH·HCl):ivDde-OH is 1:1.2.

[0046] Furthermore, the reaction temperature of the addition reaction is room temperature, and the reaction time is 2-10 hours. The reaction temperature is preferably 25° C. and the reaction time is preferably 5 hours.

[0047] Step S3, making the N α -Fluorenylmethoxycarbonyl-N γ -[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl]-L-lysine silyl ester undergoes a hydrolysis reaction to generate Fmoc-L-Lys(ivDde)-OH.

[0048] That is to say, after the addition reaction is completed, the silyl ether needs to be removed by hydrolysis to obtain the target product Fmoc-L-Lys(ivDde)-OH.

[0049] Further, the hydrolysis reaction comprises:

[0050] After the addition reaction is completed, ice water is added to quench the reaction, and an acid aqueous solution is added to cause the hydrolysis reaction. The acid aqueous solution includes any one or more of a hydrochloric acid aqueous solution, an acetic acid aqueous solution, and a sulfuric acid aqueous solution.

[0051] That is, the silyl ether group can be simply removed by hydrolysis with an acid aqueous solution. In addition, the preparation method of the present invention can actually be a one-pot method, without the need to replace the reaction equipment in the middle, and without the need to treat the intermediate product, the operation is simple, and less three wastes are produced.

[0052] Specifically, the reaction formula of the hydrolysis reaction is shown in the following formula (3), and the structural formula of Fmoc-L-Lys(ivDde)-OH is shown in “III”:

[0053] .

[0054] In some embodiments of the present invention, after the hydrolysis reaction is completed, the steps of liquid separation, drying, evaporating the solvent, and purifying the obtained crude product by column chromatography to obtain the Fmoc-L-Lys(ivDde)-OH are further included.

[0055] Since the preparation method of the present invention effectively avoids the interference caused by "by-products" and "impurities" in the existing methods, not only the yield is high, but also the final purification process becomes simple and easy to operate.

[0056] The preparation method of Fmoc-L-Lys(ivDde)-OH of the present invention is further described in detail below through specific examples.

[0057] Example 1

[0058] In a 250 mL three-necked flask, 10.00 g of Fmoc-L-Lys-OH·HCl was dissolved in 100 mL of dichloromethane. In an ice-water bath, 7.02 g of DIEA and 2.95 g of trimethylsilyl chloride were added dropwise in sequence, and the mixture was reacted at this temperature for 3 h.

[0059] Then, 6.65 g of 2-(1-hydroxy-3-methylbutenyl)-5,5-dimethyl-1,3-cyclohexanedione was added dropwise, and the temperature was raised to 25°C for reaction for 5 h;

[0060] Then, 50 mL of ice water was added to quench the reaction, and the pH was adjusted to 3 with 6N hydrochloric acid and stirred for 20 min. The mixture was separated, dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude product was purified by column chromatography to obtain 12.24 g of Fmoc-L-Lys(ivDde)-OH with a yield of 86.2%.

[0061] The product was subjected to a nuclear magnetic resonance experiment to confirm the product structure, and the data are as follows: 1H NMR (400 MHz, MeOD) δ7.79 (d, J = 7.5 Hz, 2H), 7.67 (t, J = 7.0 Hz, 2H), 7.38 (t, J = 7.5 Hz, 2H),7.30 (t, J = 7.4 Hz, 2H), 4.43 – 4.28 (m, 2H), 4.26 – 4.14 (m, 2H), 3.54 (t, J = 6.7 Hz, 2H), 3.02 (d, J = 7.0 Hz, 2H), 2.29 (s, 4H), 1.91 (dt, J = 13.3,6.6 Hz, 2H), 1.75 (dd, J = 13.9, 5.6 Hz, 3H), 1.55 (d, J = 5.9 Hz, 2H), 0.98(d, J = 3.7 Hz, 12H);

[0062] The detection results were consistent with the structure of Fmoc-L-Lys(ivDde)-OH.

[0063] Example 2

[0064] In a 250 mL three-necked flask, dissolve 10.00 g of Fmoc-L-Lys-OH·HCl in 100 mL of dichloromethane. Add 5.00 g of triethylamine and 2.95 g of trimethylsilyl chloride dropwise in an ice-water bath, and react at this temperature for 3 h.

[0065] Then, 6.65 g of 2-(1-hydroxy-3-methylbutenyl)-5,5-dimethyl-1,3-cyclohexanedione was added dropwise, and the temperature was raised to 25°C for reaction for 5 h;

[0066] Next, 50 mL of ice water was added to quench the reaction, and then the pH was adjusted to 2 with 6N hydrochloric acid and stirred for 20 min. The mixture was separated, dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained crude product was purified by column chromatography to obtain 11.71 g of Fmoc-L-Lys(ivDde)-OH with a yield of 82.5%.

[0067] The product was subjected to a nuclear magnetic resonance experiment to confirm the product structure, and the result was consistent with the structure of Fmoc-L-Lys(ivDde)-OH. The detailed description is omitted here.

[0068] Example 3

[0069] In a 250 mL three-necked flask, 10.00 g of Fmoc-L-Lys-OH was dissolved in 100 mL of dichloromethane. In an ice-water bath, 4.21 g of DIEA was added dropwise, followed by 4.5 g of tert-butyldimethylsilyl chloride. The mixture was reacted at this temperature for 3 h.

[0070] Then, 7.31 g of 2-(1-hydroxy-3-methylbutenyl)-5,5-dimethyl-1,3-cyclohexanedione was added dropwise, and the temperature was raised to 25°C for reaction for 5 h;

[0071] Next, 50 mL of ice water was added to quench the reaction, and then the pH was adjusted to 3 with 6N hydrochloric acid and stirred for 20 min. The mixture was separated, dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained crude product was purified by column chromatography to obtain 13.01 g of Fmoc-L-Lys(ivDde)-OH with a yield of 83.4%.

[0072] The product was subjected to a nuclear magnetic resonance experiment to confirm the product structure, and the result was consistent with the structure of Fmoc-L-Lys(ivDde)-OH. The detailed description is omitted here.

[0073] Example 4

[0074] In a 250 mL three-necked flask, dissolve 10.00 g of Fmoc-L-Lys-OH in 100 mL of dichloromethane. Add 4.21 g of N,N-diisopropylethylamine and 3.24 g of trimethylsilyl chloride dropwise in an ice-water bath. Heat to 25°C and react for 3 h.

[0075] Then, 7.31 g of 2-(1-hydroxy-3-methylbutenyl)-5,5-dimethyl-1,3-cyclohexanedione was added dropwise and reacted at this temperature for 5 h;

[0076] Next, 50 mL of ice water was added to quench the reaction, and then the pH was adjusted to 3 with 6N hydrochloric acid and stirred for 20 min. The mixture was separated, dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained crude product was purified by column chromatography to obtain 12.26 g of Fmoc-L-Lys(ivDde)-OH with a yield of 78.6%.

[0077] The product was subjected to a nuclear magnetic resonance experiment to confirm the product structure, and the result was consistent with the structure of Fmoc-L-Lys(ivDde)-OH. The detailed description is omitted here.

[0078] In summary, a method for preparing N α -Fluorenylmethoxycarbonyl-N γThe method of -[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl]-L-lysine has the advantages of mild reaction conditions, strong route feasibility and high yield.

[0079] The above is a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing Fmoc-L-Lys(ivDde)-OH, characterized in that: The steps include: Step S1, make N α -Fluorenylmethoxycarbonyl-L-lysine radical compound undergoes esterification reaction with trialkylchlorosilane to generate N α -Fluorenylmethoxycarbonyl-L-lysine silyl ester, the N α -Fluorenylmethoxycarbonyl-L-lysine root compound is N α -Fluorenylmethoxycarbonyl-L-lysine and / or N α -Fmoc-L-lysine hydrochloride; Step S2, making the N α -Fluorenylmethoxycarbonyl-L-lysine silyl ester reacts with 2-(1-hydroxy-3-methylbutenyl)-5,5-dimethyl-1,3-cyclohexanedione to generate N α -Fluorenylmethoxycarbonyl-N γ -[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl]-L-lysine silyl ester; Step S3, making the N α -Fluorenylmethoxycarbonyl-N γ -[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl]-L-lysine silyl ester undergoes hydrolysis to generate Fmoc-L-Lys(ivDde)-OH, wherein Fmoc-L-Lys(ivDde)-OH is N α -Fluorenylmethoxycarbonyl-N γ -[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl]-L-lysine, wherein the trialkylchlorosilane is any one or more of trimethylchlorosilane, triethylchlorosilane, and tert-butyldimethylchlorosilane, The esterification reaction is carried out in an organic solvent under the action of an organic base, wherein the organic solvent is selected from any one or more of dichloromethane, tetrahydrofuran, 1,2-dichloroethane, and N,N-dimethylformamide, and the organic base is N,N-diisopropylethylamine.

2. The preparation method according to claim 1, characterized in that: The N α The molar ratio of -fluorenylmethoxycarbonyl-L-lysine root compound:trialkylchlorosilane:organic base is 1:(1.0-1.5):(1.0-2.5).

3. The preparation method according to claim 1, characterized in that The reaction temperature of the esterification reaction is -5~40°C, and the reaction time is 2~8 h.

4. The preparation method according to claim 1, characterized in that: The step S2 comprises: After the esterification reaction is completed, the 2-(1-hydroxy-3-methylbutenyl)-5,5-dimethyl-1,3-cyclohexanedione is added dropwise into the reaction system to cause the addition reaction.

5. The preparation method according to claim 4, characterized in that: The N α The molar ratio of -fluorenylmethoxycarbonyl-L-lysine root compound:2-(1-hydroxy-3-methylbutenyl)-5,5-dimethyl-1,3-cyclohexanedione is 1:(1.0-1.5).

6. The preparation method according to claim 5, characterized in that: The reaction temperature of the addition reaction is room temperature, and the reaction time is 2-10 hours.

7. The preparation method according to claim 1, characterized in that: The hydrolysis reaction comprises: After the addition reaction is completed, ice water is added to quench the reaction, and an acid aqueous solution is added to a pH of 2-3 to cause the hydrolysis reaction, wherein the acid aqueous solution is selected from any one or more of a hydrochloric acid aqueous solution, an acetic acid aqueous solution, and a sulfuric acid aqueous solution.

8. The preparation method according to claim 7, characterized in that: After the hydrolysis reaction is completed, the steps include liquid separation, drying, evaporating the solvent, and purifying the obtained crude product by column chromatography to obtain the Fmoc-L-Lys(ivDde)-OH.