A method for synthesizing elastatin and its intermediates

Abstract

The present invention provides a method for synthesizing alacastran, comprising reacting an amino compound of formula V with a chiral intermediate of formula VI, reducing the resulting product with a reducing agent capable of providing an ethyl group to produce a compound of formula VII, and then deprotecting the compound to obtain alacastran, as shown in the following reaction formula. The method for synthesizing alacastran of the present invention avoids the low yield caused by amide reduction and the risk of substrate racemization, has a high yield, low material cost, safe operation, and is suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the field of raw material drug synthesis, and more specifically, relates to a method for synthesizing elastomeric (Elacestrant) and its intermediates. Background Art

[0002] Elacestrant is an ER degrader (SERD) developed by Menarini for the treatment of advanced or metastatic breast cancer in postmenopausal women or men with ER+, HER2-, or ESR1 mutations who have progressed after at least one prior endocrine therapy. It was approved for marketing by the FDA on January 27, 2023, under the trade name ORSERDU (oral tablets, 86 mg, 345 mg). Its structure is shown below:

[0003]

[0004] Regarding the synthesis of elastatin, there are currently only two routes reported by the original research company. The first route is the synthesis route reported in the prior art WO2004058682:

[0005]

[0006] In this route, compound A3 is obtained by coupling compounds A1 and A2, and then compound A4 is obtained by Pd / C catalytic reduction. Compound A4 is a racemate and requires chiral resolution in the fifth step, with a maximum yield of only 50%. The third and seventh steps of this route both reduce the amide group to the corresponding amine via lithium aluminum hydride, which not only has a low yield but also uses a dangerous reagent, lithium aluminum hydride. The raw material A8 used is also an unconventional material, with no industrialized product on the market and no suitable synthetic method for producing this raw material.

[0007] In 2020, the prior art WO2020167855 reported the second route:

[0008]

[0009] Compared with the first route, the final product yield of this route has been significantly improved, but the overall yield is still low (total yield 12.75%). The reason is that this route still requires chiral resolution to obtain a single-configuration intermediate, and the yield of the fifth-step resolution reaction is only 45%; the final step of the amide reduction reaction has a yield of only 50% after purification because the substrate has chirality and sensitive functional groups, the optional reducing reagents are limited, and the product has the risk of racemization; the raw material B6 is also an unconventional material, and there is no industrialized product on the market.

[0010] In summary, existing methods for synthesizing elastostat cannot achieve asymmetric reduction, resulting in low yields. Furthermore, they require hazardous reagents and specialized equipment, making them unsuitable for industrialization and resulting in high product costs. Therefore, there is an urgent need in the art to develop a low-cost, high-yield, simple-to-operate method for synthesizing elastostat that is suitable for industrialization. Summary of the Invention

[0011] In view of the defects of the prior art methods for synthesizing elastostat, the present invention provides a novel method for synthesizing elastostat, which comprises the following steps:

[0012] (1) reacting a compound of formula V with a compound of formula VI, and reducing the resulting product with a reducing agent to produce a compound of formula VII, wherein the reducing agent also provides an ethyl group, as shown in the following reaction formula:

[0013]

[0014] Wherein said reaction formula R2 is a nitrogen protecting group, R3 is H or a hydroxyl protecting group,

[0015] (2) removing the nitrogen protecting group from the compound of formula VII to obtain elastostat, wherein the protecting group is a nitrogen protecting group and a hydroxyl protecting group, or is a nitrogen protecting group.

[0016] In another preferred embodiment, in step (1), the compound of formula V reacts with the compound of formula VI at 50-80° C. to form a Schiff base, which is then reduced by the reducing agent at 40-70° C. and an ethyl group is introduced to obtain the compound of formula VII.

[0017] In another preferred embodiment, the reaction of generating the Schiff base is carried out in a solvent selected from toluene, tetrahydrofuran, methyltetrahydrofuran or a combination thereof. In another preferred embodiment, the reaction of reducing the Schiff base and introducing the ethyl group is carried out in a solvent selected from toluene, tetrahydrofuran, methyltetrahydrofuran or a combination thereof.

[0018] In another preferred embodiment, the molar ratio of the compound of formula VI to the compound of formula V is 1:1 to 1.2.

[0019] In another preferred embodiment, the reducing agent used in the reaction of step (1) is selected from sodium triacetoxyborohydride.

[0020] In another preferred embodiment, the nitrogen protecting group is selected from Boc or Fmoc.

[0021] In another preferred embodiment, the hydroxyl protecting group is selected from Bn, Cbz or Ac.

[0022] In another preferred embodiment, in step (2), when R3 is H, the nitrogen protecting group of the compound of formula VII is removed to obtain alacastran. In another preferred embodiment, in step (2), when R3 is a hydroxy protecting group, the nitrogen protecting group and the hydroxy protecting group of the compound of formula VII are removed in sequence, or the hydroxy protecting group and the nitrogen protecting group of the compound of formula VII are removed in sequence to obtain alacastran.

[0023] In another preferred embodiment, in the synthesis method of elastostat, the synthesis method of the compound of formula V comprises the steps of converting R1 in the compound of formula IV into an aldehyde group to obtain the compound of formula V, and the reaction formula is as follows:

[0024]

[0025] In the reaction formula, R1 is selected from bromine or iodine, and R2 is a nitrogen protecting group.

[0026] In another preferred embodiment, the conversion of R1 in the compound of formula IV into an aldehyde group is carried out in the presence of a strong base reagent, wherein the strong base reagent is selected from n-butyllithium, tert-butyllithium, metallic lithium, more preferably n-butyllithium.

[0027] In another preferred embodiment, the conversion of R1 in the compound of formula IV into an aldehyde group is carried out in the presence of a metal catalyst, wherein the metal catalyst is a palladium-containing catalyst selected from palladium acetate, tetrakistriphenylphosphine palladium, Pd(dppf)Cl2, and Pd(dba)2.

[0028] Another aspect of the present invention provides a method for synthesizing a compound of formula V, comprising the following steps:

[0029] (1) condensing the compound of formula I with ethylamine to obtain compound II;

[0030] (2) reducing the compound of formula II to obtain the compound of formula III;

[0031] (3) protecting the amino group of the compound of formula III to obtain a compound of formula IV;

[0032] (4) converting R1 of the compound of formula IV into an aldehyde group to obtain a compound of formula IV,

[0033] The reaction formula is as follows:

[0034]

[0035] In the reaction formula, R1 is selected from bromine or iodine, and R2 is a nitrogen protecting group.

[0036] In another aspect, the present invention provides a method for synthesizing elastatin, comprising the following steps:

[0037] (1) reacting a compound of formula V with a compound of formula VI, and reducing the resulting product with a reducing agent to produce a compound of formula VII, wherein the reducing agent also provides an ethyl group, as shown in the following reaction formula:

[0038]

[0039] Wherein, R2 is a nitrogen protecting group, R3 is H or a hydroxyl protecting group,

[0040] (2) removing the protecting group of the compound of formula VII to obtain elastostat, wherein the protecting group is a nitrogen protecting group and a hydroxyl protecting group, or a nitrogen protecting group,

[0041] The compound of formula V is obtained according to the synthesis method of the compound of formula V above. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 The compound of formula II-1 obtained in Example 1 1 H-NMR spectrum;

[0043] Figure 2 The compound of formula III-1 obtained in Example 1 1 H-NMR spectrum;

[0044] Figure 3 The compound of formula IV-1 obtained in Example 1 1 H-NMR spectrum;

[0045] Figure 4 The compound of formula V-1 obtained in Example 1 1 H-NMR spectrum;

[0046] Figure 5 The compound of formula VII-1 obtained in Example 2 1 H-NMR spectrum;

[0047] Figure 6 This is the HPLC spectrum of the compound of formula VII-1 obtained in Example 2;

[0048] Figure 7 The Elacestrant compound obtained in Example 2 1 H-NMR spectrum;

[0049] Figure 8 This is the HPLC spectrum of the Elacestrant compound obtained in Example 2;

[0050] Figure 9 This is the mass spectrum of the Elacestrant compound obtained in Example 2. DETAILED DESCRIPTION

[0051] To address the shortcomings of prior art methods for synthesizing elastostat, the inventors of this application, through in-depth research, discovered that in the synthesis of elastostat, a method using an amide-free intermediate compound (Formula V) and a chiral intermediate compound (Formula VI) containing a tetralin ring undergoes reductive amination to obtain the elastostat structure, avoiding the low yields and risk of substrate racemization caused by amide reduction. This synthetic method offers high yields and low costs throughout the entire route, significantly reducing the cost of the API.

[0052] Synthesis method of compound of formula V

[0053] In the present invention, the synthesis method of the compound of formula V comprises the following steps:

[0054] (1) subjecting the compound of formula I to a condensation reaction with ethylamine to obtain compound II;

[0055] (2) reducing the compound of formula II to obtain the compound of formula III;

[0056] (3) protecting the amino group of the compound of formula III to obtain a compound of formula IV;

[0057] (4) converting R1 in the compound of formula IV into an aldehyde group to obtain a compound of formula IV,

[0058] The reaction formula is as follows:

[0059]

[0060] In the above reaction formula, R1 is bromine or iodine, and R2 is a nitrogen protecting group.

[0061] In step (1), the condensing agent used in the condensation reaction is a condensing agent commonly used for this type of reaction, and can be selected from EDCI, DCC, HOBt, CDI, HBTu, or a combination thereof. The reaction solvent is a solvent commonly used for this type of reaction, and can be selected from dichloromethane, N,N-dimethylformamide, dimethyl sulfoxide, toluene, tetrahydrofuran, and more preferably, a mixed solvent of dichloromethane and N,N-dimethylformamide. The molar ratio of the reaction raw material ethylamine to the compound of formula I is preferably 0.8 to 4:1; more preferably 1.2:1. During the addition process, the temperature of the reaction system is controlled to be 0 to 15°C. After the addition is completed, the reaction system reacts at room temperature until the compound of formula I is completely converted.

[0062] In step (2), the reducing agent used for the amide reduction is a reducing agent commonly used for this type of reaction, and can be selected from borane, a borane complex, lithium aluminum hydride, sodium borohydride, sodium borohydride, a Lewis acid, or a combination thereof, more preferably borane dimethyl sulfide and / or lithium aluminum hydride. The reaction solvent is a solvent commonly used for this type of reaction, and can be selected from tetrahydrofuran, toluene, 1,4-dioxane, dichloromethane, or a combination thereof, more preferably tetrahydrofuran. The molar ratio of the reducing agent to the substrate compound of formula II is 1 to 5:1; more preferably 2:1. The reduction reaction temperature is -70 to 80°C; preferably, 30 to 70°C.

[0063] In step (3), amino protection is a common reaction in the art. The reaction is carried out in the presence of a base, such as triethylamine, at 0 to 40°C. The reagent providing the amino protecting group is preferably selected from di-tert-butyl dicarbonate or 9-fluorenylmethyl chloroformate; more preferably di-tert-butyl dicarbonate. The reaction solvent is a commonly used solvent for this type of reaction, and can be selected from 1,4-dioxane, dichloromethane, dimethyl sulfoxide, toluene, and tetrahydrofuran.

[0064] In step (4), in some specific embodiments, the reaction of introducing an aldehyde group into the compound of formula IV is carried out in the presence of a strong base. The strong base reagent is preferably selected from n-butyl lithium, tert-butyl lithium, metallic lithium, and more preferably n-butyl lithium. The reaction temperature is -80 to -60°C, and the molar ratio of the strong base reagent to the compound of formula IV is 1 to 5:1. The solvent used in the reaction of introducing the aldehyde group can be selected from tetrahydrofuran, methyltetrahydrofuran, and toluene.

[0065] In other specific embodiments, the reaction of introducing an aldehyde group into the compound of Formula IV is carried out in the presence of a metal catalyst, wherein the metal catalyst is a palladium-containing catalyst, preferably selected from palladium acetate, tetrakistriphenylphosphine palladium, Pd(dppf)Cl2, and Pd(dba)2. The reaction temperature is -80°C to -60°C. The amount of palladium catalyst used in the reaction is 0.002 to 0.1 equivalents. The solvent used in the reaction can be selected from toluene and tetrahydrofuran.

[0066] Synthesis method of elastostat

[0067] The synthesis method of elastatin comprises the following steps:

[0068] (1) reacting a compound of formula V with a compound of formula VI, and reducing the resulting product with a reducing agent to produce a compound of formula VII, wherein the reducing agent also provides an ethyl group, as shown in the following reaction formula:

[0069]

[0070] In the above reaction formula, R2 is a nitrogen protecting group, R3 is H or a hydroxyl protecting group,

[0071] (2) removing the protecting group of the compound of formula VII to obtain elastostat, wherein the protecting group is a nitrogen protecting group and a hydroxyl protecting group, or a nitrogen protecting group.

[0072] In step (1), the compound of formula V reacts with the compound of formula VI to form a Schiff base. The Schiff base is reduced by a reducing agent and an ethyl group is introduced to form a compound of formula VII, wherein the reducing agent is preferably selected from sodium triacetoxyborohydride. The reaction to form the Schiff base is carried out at 50-80°C, more preferably 60-70°C. The solvent used in this step can be selected from tetrahydrofuran, toluene, 1,4-dioxane, methyltetrahydrofuran, or a combination thereof; preferably, tetrahydrofuran. The molar ratio of the compound of formula VI to the compound of formula V is 1:1-1.2.

[0073] The reduction and introduction of the ethyl group is carried out at 40-70° C., more preferably 50-60° C. Preferably, after the compound of formula V reacts with the compound of formula VI to form a Schiff base, the reaction solution is concentrated until no obvious fraction remains, and then a solvent and a reducing agent are added to reduce the Schiff base and introduce an amino group.

[0074] In step (2), when R3 is a hydroxyl protecting group, the hydroxyl protecting group and the nitrogen protecting group are removed from the compound of formula V to obtain alacastran; when R3 is H, the nitrogen protecting group is removed from the compound of formula VII to obtain alacastran. The hydroxyl protecting group and the nitrogen protecting group can be removed according to conventional methods for the specific protecting groups. For example, the nitrogen protecting group Boc can be removed under acidic conditions, such as with the addition of triethylamine, and the hydroxyl protecting group Bn can be removed in the presence of Pd / C. There is no time sequence for the removal of the hydroxyl protecting group and the nitrogen protecting group. The hydroxyl protecting group can be removed first and then the nitrogen protecting group, or the nitrogen protecting group can be removed first and then the hydroxyl protecting group.

[0075] In one embodiment of the present invention, the method for synthesizing elastatin comprises the following steps:

[0076] (1) subjecting the compound of formula I to a condensation reaction with ethylamine to obtain compound II;

[0077] (2) reducing the compound of formula II to obtain the compound of formula III;

[0078] (3) protecting the amino group of the compound of formula III to obtain a compound of formula IV;

[0079] (4) converting R1 in the compound of formula IV into an aldehyde group to obtain a compound of formula IV;

[0080] (5) reacting the compound of formula V with the compound of formula VI, and reducing the resulting product with a reducing agent to produce a compound of formula VII, wherein the reducing agent also provides an ethyl group;

[0081] (6) removing the protecting group of the compound of formula VII to obtain elastostat, wherein the protecting group is a nitrogen protecting group and a hydroxyl protecting group, or a nitrogen protecting group,

[0082] The reaction formula is as follows:

[0083]

[0084] In the above reaction formula, R1 is bromine or iodine, R2 is a nitrogen protecting group, and R3 is H or a hydroxyl protecting group.

[0085] Compared with the prior art, the advantages of the synthesis method of elastomeric of the present invention are:

[0086] 1) Short steps, simple and efficient, easy to industrialize;

[0087] 2) The introduction of the amino group in advance avoids the low yield and risk of product racemization caused by the final step of amide reduction;

[0088] 3) All reaction steps involved are conventional reactions, and the material prices are low, which greatly reduces the cost of API;

[0089] 4) Each reaction step has a high yield. For example, the six-step reaction from 4-bromophenylacetic acid to elastostat has a yield of 61.7%, significantly higher than that of existing technologies. The final product has a purity greater than 99%.

[0090] The present invention is further described in detail below with reference to specific examples, and the protection content of the present invention is not limited to the following examples. The processes, conditions, reagents, experimental methods, etc. in the following examples, except for the contents specifically mentioned below, are common knowledge and common common sense in the art, and the present invention has no special restrictions. Unless otherwise specified, the raw materials used in the present invention are commercially available or can be prepared according to prior art. For example, the compound of formula VI-1 mentioned below can be prepared according to the method reported in prior art WO2020167855.

[0091] Example 1 Synthesis of the compound of formula V-1 (in the compound of formula V, R2 = Boc)

[0092]

[0093] Step 1, add DMF (0.4L), dichloromethane (0.8L), formula I-1 compound (200.0g) to the reactor, cool to 0-10°C, add ethylamine hydrochloride (91.0g), EDCI (214.0g), control the temperature at 0-10°C, add DIPEA (282.5g) dropwise, raise the temperature to 20-30°C, after the raw materials are completely converted, concentrate, add water to the concentrate to precipitate the product, cool and filter, dry to obtain 212.1g of solid compound of formula II-1, with a yield of 94.5% ( Figure 1 : 1 H-NMR).

[0094] Step 2, tetrahydrofuran (0.9 L), compound of formula II-1 (180.0 g) were added to the reaction kettle, the temperature control system T≤30°C, 2.0 M borane dimethyl sulfide complex (929 mL) was added dropwise, and after the addition was completed, the temperature was raised to 50-60°C. After the raw material conversion was complete, the system was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic phase was washed once with a saturated sodium chloride aqueous solution, and the organic phase was concentrated to dryness to obtain 60.0 g of compound of formula III-1 as an oily product with a yield of 94.8% ( Figure 2 : 1 H-NMR).

[0095] Step 3, add 1,4-dioxane (0.8L), compound of formula III-1 (160.0g), triethylamine (108.4g), di-tert-butyl dicarbonate (186.9g) to the reactor, monitor the complete conversion of the raw materials by TLC, concentrate, add water to the concentrate, add ethyl acetate, extract twice, wash the organic phase with saturated sodium chloride aqueous solution once, and concentrate the organic phase to dryness to obtain 217.1g of oily product compound of formula IV-1, with a yield of 93.3% ( Figure 3 : 1 H-NMR).

[0096] Step 4, add tetrahydrofuran (1.1L), formula IV-1 compound (217.0g) to the reaction kettle, cool to -78 ° C, add n-butyl lithium (296mL) dropwise, control the temperature at -80 to -75 ° C, stir for 0.5 to 1h, add N, N-dimethylformamide (162.3g) dropwise, control the temperature at -80 to -75 ° C to react, after the raw material conversion is complete, add saturated ammonium chloride solution dropwise to the system, add water, stir, separate the liquid, extract the aqueous phase with ethyl acetate, combine the organic phases, and wash once with saturated sodium chloride aqueous solution, and concentrate the organic phase to dryness to obtain 161.9g of oily product formula V-1 compound, with a yield of 87.2% ( Figure 4 : 1 H-NMR).

[0097] Example 2 Synthesis of Elastran

[0098]

[0099] To the reactor, tetrahydrofuran (1.5 L), n-heptane (0.75 L), compound of formula VI-1 (R3=H in compound of formula V) (100.0 g), compound of formula V-1 (123.4 g), D-dibenzoyltartaric acid (0.1 g) were added, and the temperature was raised to 60-70° C. for reaction, and the conversion of the raw materials was monitored to be complete. The mixture was concentrated until no obvious fraction was found. Tetrahydrofuran (1.5 L) and sodium triacetylborohydride (354.1 g) were added, and the temperature was raised to 50-60° C. for reaction, and after the conversion of the raw materials was monitored to be complete, the system was cooled to 20-30° C., water was added, and the liquids were separated. The aqueous phase was extracted with ethyl acetate with 5 times the volume of water, and the organic phases were combined and concentrated to dryness to obtain a crude product. The crude product was purified by silica gel column to obtain 84.5 g of compound of formula VII-11 as an oily product with a yield of 89.2% and a HPLC purity of 94.36% ( Figure 5 : 1 H-NMR, Figure 6 :HPLC).

[0100] Ethyl acetate (1.0 L), compound of formula VII-1 (100.0 g, 179.2 mmol), and 2M hydrochloric acid in ethyl acetate (448 mL) were added to the reaction kettle and the reaction was carried out at a temperature of 20-30 ° C. The raw materials were completely converted, and the temperature was lowered to 0-10 ° C., filtered, and dried to obtain 90.4 g of solid with a yield of 95.0% and a HPLC purity of 99.33% ( Figure 7 : 1 H-NMR, MeOH+NaOD, Figure 8 :HPLC, Figure 9 : mass spectrometry).

[0101] Example 3 Synthesis of Elastran

[0102]

[0103] Methyltetrahydrofuran (1.4 L), n-heptane (1 L), compound VI-2 (R3 = Bn in the compound of formula VI) (135.3 g), compound V-1 (125.1 g), D-dibenzoyltartaric acid (0.15 g) were added to the reactor, and the temperature was raised to 70-80 ° C for reaction. After the raw material conversion was complete, the reaction mixture was concentrated, and methyltetrahydrofuran (2 L) and sodium triacetylborohydride (377.1 g) were added. The temperature was raised to 60-70 ° C for reaction. After the raw material conversion was complete, the temperature was lowered to 20-30 ° C. Water was added to the reaction solution, the liquid was separated, the aqueous phase was extracted with isopropyl acetate, the organic phases were combined, and the organic phases were concentrated to dryness to obtain a crude product. The crude product was purified by silica gel column to obtain 200.5 g of the oily product compound of formula VII-2 with a yield of 83.2%.

[0104] The compound of formula VII-2 (120 g, 1.0 eq.) and methanol (1.2 L) were added to the reaction kettle, and the temperature was lowered to 0-10°C. Trifluoroacetic acid (63.3 g, 3.0 eq.) was added dropwise. After the reaction was complete, the mixture was concentrated, water was added, and the pH was adjusted to 9-10 with aqueous NaOH solution. The mixture was filtered and dried under vacuum to obtain the compound of formula VII-3 (91.8 g, yield: 90.4%).

[0105] To a hydrogenation reactor was added the compound of formula VII-3 (91.7 g), methanol (0.92 L), and 5% Pd / C (2.3 g, 5 wt%). The reaction was carried out at 30-40 psi for 8-10 hours. After the reaction was complete, the mixture was filtered. An aqueous HCl solution (42.3 g) was added to the mother liquor, which was concentrated to 5-6 volumes, filtered, and dried under vacuum to obtain 83.4 g of elastatin with a yield of 94.2%.

[0106] Example 4 Synthesis of Elastran

[0107]

[0108] Add the compound of formula VII-2 (120 g, 0.185 mol., 1.0 eq.), methanol (1.2 L, 10 volumes), 10% Pd / C (1.5 g, 2.5 wt%) to the hydrogenation reactor, react at 35-45 psi, react at 40-45°C, and after the reaction is completed, filter and concentrate the mother liquor to obtain 123.1 g of a crude product of the compound of formula VII-4.

[0109] Add 123.1 g of crude VII-4 to the reaction flask, add 93.8 g of HCl aqueous solution at room temperature, heat to 50-60°C, react for 3-4 hours, and complete the reaction by TLC. Concentrate to 5 volumes, filter, and dry in vacuo to obtain 84.2 g of the product with a yield of 85.9%.

[0110] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A method for synthesizing elastostat or a salt thereof, characterized in that: The synthesis method comprises the steps of: (1) The compound of formula V reacts with the compound of formula VI, and the resulting product is reduced with a reducing agent to produce a compound of formula VII, wherein the reducing agent is sodium triacetoxyborohydride, and the reaction formula is as follows: Wherein, R2 is a nitrogen protecting group, R3 is H or a hydroxyl protecting group, (2) removing the protecting group of the compound of formula VII to obtain elastostat, wherein the protecting group is a nitrogen protecting group and a hydroxyl protecting group, or a nitrogen protecting group, In step (1), the compound of formula V reacts with the compound of formula VI at 50-80° C. to form a Schiff base, which is then reduced by the reducing agent at 40-70° C. and an ethyl group is introduced to obtain the compound of formula VII.

2. The method for synthesizing elastatin or a salt thereof according to claim 1, wherein: The reaction to form the Schiff base is carried out in a solvent selected from the group consisting of: Toluene, tetrahydrofuran, methyltetrahydrofuran, or a combination thereof, and / or The reaction of reducing the Schiff base and introducing an ethyl group is carried out in a solvent selected from the following: Toluene, tetrahydrofuran, methyltetrahydrofuran, or a combination thereof, and / or The molar ratio of the compound of formula VI to the compound of formula V is 1:1 to 1.

2.

3. The method for synthesizing elastostat or a salt thereof according to claim 1, wherein: The nitrogen protecting group is selected from Boc or Fmoc, and / or The hydroxy protecting group is selected from Bn, Cbz or Ac.

4. The method for synthesizing elastatin or a salt thereof according to claim 1, characterized in that: In step (2), When R3 is H, the compound of formula VII is denitrified to obtain elastostat; When R3 is a hydroxy protecting group, the nitrogen protecting group and the hydroxy protecting group are sequentially removed from the compound of formula VII, or the hydroxy protecting group and the nitrogen protecting group are sequentially removed from the compound of formula VII to obtain elastostat.

5. The method for synthesizing elastostat or a salt thereof according to claim 1, wherein: The synthesis method of the compound of formula V comprises the steps of converting R1 in the compound of formula IV into an aldehyde group to obtain the compound of formula V, and the reaction formula is as follows: In the reaction formula, R1 is selected from bromine or iodine, and R2 is a nitrogen protecting group.

6. The method for synthesizing elastostat or a salt thereof according to claim 5, characterized in that: The conversion of R1 into an aldehyde group in the compound of formula IV is carried out in the presence of a strong base reagent or a metal catalyst. The strong base reagent is selected from n-butyl lithium, tert-butyl lithium, metallic lithium, The metal catalyst is a palladium-containing catalyst, and the palladium-containing catalyst is selected from palladium acetate, tetrakistriphenylphosphine palladium, Pd(dppf)Cl2, and Pd(dba)2.

7. The method for synthesizing elastatin or a salt thereof according to claim 6, characterized in that: The strong base reagent is selected from n-butyl lithium.

8. The method for synthesizing elastostat or a salt thereof according to claim 1, wherein: The synthesis method of the compound of formula V comprises the following steps: (1) condensing the compound of formula I with ethylamine to obtain compound II; (2) reducing the compound of formula II to obtain the compound of formula III; (3) protecting the amino group of the compound of formula III to obtain a compound of formula IV; (4) converting R1 of the compound of formula IV into an aldehyde group to obtain a compound of formula V, The reaction formula is as follows: In the reaction formula, R1 is selected from bromine or iodine, and R2 is a nitrogen protecting group.

9. A method for synthesizing elastostat or a salt thereof, characterized in that: The synthesis method comprises the following steps: (1) reacting a compound of formula V with a compound of formula VI to form a Schiff base, and reducing the resulting Schiff base product with a reducing agent to form a compound of formula VII, wherein the reducing agent is sodium triacetoxyborohydride, according to the following reaction formula: Wherein, R2 is a nitrogen protecting group, R3 is a hydroxyl protecting group, (2) removing the protecting group of the compound of formula VII to obtain elastostat, wherein the protecting group is a nitrogen protecting group and a hydroxyl protecting group, or a nitrogen protecting group; The synthesis method of the compound of formula V comprises the following steps: (1) condensing the compound of formula I with ethylamine to obtain compound II; (2) reducing the compound of formula II to obtain the compound of formula III; (3) protecting the amino group of the compound of formula III to obtain a compound of formula IV; (4) converting R1 of the compound of formula IV into an aldehyde group to obtain a compound of formula V, The reaction formula is as follows: In the reaction formula, R1 is selected from bromine or iodine, and R2 is a nitrogen protecting group.

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