Synthesis method of alasset and intermediates of alasset
By reducing and amination of the intermediate V compound without amide and chiral intermediate VI compound containing tetrahydronaphthalene ring, the existing arasent synthesis method has solved the problem of low yield and use of dangerous reagents, and achieved high yield and low cost synthesis, which is suitable for industrial production.
Patent Information
- Application Number
- CN202311178672.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2023-09-13
- Publication Date
- 2025-03-14
- Estimated Expiration
- 2043-09-13
AI Technical Summary
The existing Alisent synthesis method has low yields, uses hazardous reagents and special equipment, is not suitable for industrialization, and has high product costs.
Reduced amination of the intermediate V compound without amide and chiral intermediate VI compound containing tetrahydronaphthalene ring to obtain the alasent structure, avoiding the low yield caused by amide reduction and the risk of substrate racemics.
It realizes high yield and low cost Alisent synthesis, reduces API costs, and simplifies the process flow, which is suitable for industrial production.
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Figure CN119613272A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the field of raw material drug synthesis, and more specifically, relates to a synthesis method of Elacestrant and its intermediates. Background Art
[0002] Elacestrant is an ERs degrader (SERD) developed by Menarini for postmenopausal women or adult men with advanced or metastatic breast cancer who have ER+, HER2-, or ESR1 mutations and have progressed after at least one line of endocrine therapy. It was approved for marketing by the FDA on January 27, 2023, with the trade name ORSERDU (oral tablets, 86 mg, 345 mg), and its structure is shown below:
[0003]
[0004] Regarding the synthesis method of elastomeric, 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 reaction of compounds A1 and A2, and compound A4 is obtained by Pd / C catalytic reduction. Compound A4 is a racemate and needs to be chiral resolved in the fifth step, with a maximum yield of only 50%. The third and seventh steps of this route are both to reduce the amide group with lithium aluminum hydride to obtain the corresponding amine, 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, there is no industrial product on the market, and there is currently no suitable synthesis method to produce 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 last 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, the prior art methods for synthesizing elastostat cannot achieve asymmetric reduction, resulting in low yield, and use hazardous reagents and special equipment, which is not suitable for industrialization and has high product cost. Therefore, there is an urgent need in the art to develop a method for synthesizing elastostat that is low-cost, high-yield, simple to operate, and 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 steps of:
[0012] (1) reacting a compound of formula V with a compound of formula VI, and reducing the resulting product with a reducing agent to generate a compound of formula VII, wherein the reducing agent also provides an ethyl group, and the reaction formula is as follows:
[0013]
[0014] Wherein R2 in the reaction formula 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 a compound of formula VII.
[0017] In another preferred embodiment, the reaction of generating 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 Schiff base and introducing 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 elastostat. 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 elastostat.
[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 to an aldehyde group is carried out in the presence of a strong base reagent, wherein the strong base reagent is selected from n-butyl lithium, tert-butyl lithium, metallic lithium, more preferably n-butyl lithium.
[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 elastomeric, the method 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 generate a compound of formula VII, wherein the reducing agent also provides an ethyl group, and the reaction formula is as follows:
[0038]
[0039] In the reaction formula, 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 elastostratum, 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 mentioned 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 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 The HPLC spectrum of the Elacestrant compound obtained in Example 2;
[0050] Fig. 9 This is the mass spectrum of the Elacestrant compound obtained in Example 2. DETAILED DESCRIPTION
[0051] In view of the defects of the synthesis method of elastostat in the prior art, the inventors of the present application have found through in-depth research that in the synthesis process of elastostat, the intermediate compound of formula V without amide and the chiral intermediate compound of formula VI containing a tetralin ring are used to obtain the elastostat structure through reductive amination, thereby avoiding the low yield caused by amide reduction and the risk of substrate racemization. The entire route of the synthesis method has high yield and low cost, which greatly reduces the cost of 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 condensation agent used in the condensation reaction is a condensation agent commonly used for such reactions, and can be selected from EDCI, DCC, HOBt, CDI, HBTu, or a combination thereof. The reaction solvent is a solvent commonly used for such reactions, 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 feeding process, the temperature of the reaction system is controlled to be 0 to 15°C. After the feeding 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 amide reduction is a reducing agent commonly used for such reactions, and can be selected from borane, borane complex, lithium aluminum hydride, sodium borohydride, sodium borohydride, Lewis acid, or a combination thereof, preferably borane dimethyl sulfide and / or lithium aluminum hydride. The reaction solvent is a solvent commonly used for such reactions, and can be selected from tetrahydrofuran, toluene, 1,4-dioxane, dichloromethane, or a combination thereof, preferably tetrahydrofuran. The molar ratio of the reducing agent to the substrate compound of formula II is 1 to 5:1; preferably 2:1. The temperature of the reduction reaction is -70 to 80°C; preferably, 30 to 70°C.
[0063] In step (3), amino protection is a common reaction in the art, and 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 such reactions, 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 an aldehyde group can be selected from tetrahydrofuran, methyltetrahydrofuran, and toluene.
[0065] In other specific embodiments, the reaction of introducing 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, and the palladium-containing catalyst is preferably selected from palladium acetate, tetrakistriphenylphosphine palladium, Pd(dppf)Cl2, Pd(dba)2. The reaction temperature is -80 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 elastostat 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 generate a compound of formula VII, wherein the reducing agent also provides an ethyl group, and the reaction formula is as follows:
[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, and 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 to 80° C., more preferably 60 to 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 to 1.2.
[0073] The reduction and introduction of ethyl groups are 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 there is no obvious fraction, 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 of the compound of formula V are removed to obtain elastostat; when R3 is H, the nitrogen protecting group of the compound of formula VII is removed to obtain elastostat. The removal of the hydroxyl protecting group and the nitrogen protecting group can be carried out according to the conventional method for the specific protecting group. For example, the nitrogen protecting group Boc can be removed under acidic conditions, for example, under the condition of adding 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 synthesis method of elastomeric 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 elastostratum, 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 elastoside 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 the risk of product racemization caused by the final step of amide reduction;
[0088] 3) All the reaction steps involved are conventional reactions, and the material price is low, which greatly reduces the API cost;
[0089] 4) The yield of each reaction step involved is high. For example, the yield of the six-step reaction of obtaining elastomeric from 4-bromophenylacetic acid as the starting material is as high as 61.7%, which is much higher than the prior art. The purity of the final product is greater than 99%.
[0090] The present invention is further described in detail below in conjunction with 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 the prior art. For example, the compound of formula VI-1 mentioned below can be prepared according to the method reported in the 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 reaction kettle, 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 material conversion is complete, 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, yield 94.5% ( Figure 1 : 1 H-NMR).
[0094] Step 2, add tetrahydrofuran (0.9L), compound of formula II-1 (180.0g) to the reaction kettle, control the temperature system T≤30℃, add 2.0M borane dimethyl sulfide complex (929mL) dropwise, and raise the temperature to 50-60℃. After the raw material conversion is complete, cool the system, add water, extract with ethyl acetate, wash the organic phase once with saturated sodium chloride aqueous solution, and concentrate the organic phase to dryness to obtain 60.0g of oily product compound of formula III-1, 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 reaction kettle, 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 once with saturated sodium chloride aqueous solution, 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), compound IV-1 (217.0g) to the reaction kettle, cool to -78°C, add n-butyl lithium (296mL) dropwise, control the temperature at -80~-75°C, stir for 0.5~1h, add N,N-dimethylformamide (162.3g) dropwise, control the temperature at -80~-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 liquids, extract the aqueous phase with ethyl acetate, combine the organic phases, and wash once with saturated sodium chloride aqueous solution, concentrate the organic phase to dryness, and obtain 161.9g of oily product compound V-1, with a yield of 87.2% ( Figure 4 : 1 H-NMR).
[0097] Example 2 Synthesis of Elastran
[0098]
[0099] Add tetrahydrofuran (1.5L), n-heptane (0.75L), compound of formula VI-1 (R3=H in compound of formula V) (100.0g), compound of formula V-1 (123.4g), D-dibenzoyltartaric acid (0.1g) to the reaction kettle, heat to 60-70°C for reaction, monitor the complete conversion of the raw materials, concentrate until there is no obvious fraction, add tetrahydrofuran (1.5L), sodium triacetylborohydride (354.1g), heat to 50-60°C for reaction, monitor the complete conversion of the raw materials, cool the system to 20-30°C, add water, separate the liquids, extract the aqueous phase with ethyl acetate with 5 times the volume of water, combine the organic phases, and concentrate the organic phases to dryness to obtain a crude product. The crude product was purified by silica gel column to obtain 84.5g of oily product compound of formula VII-11, with a yield of 89.2% and an 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), 2M hydrochloric acid in ethyl acetate solution (448 mL) were added to the reaction kettle, and the temperature was controlled at 20-30 ° C. The raw material was 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, Fig. 9 : mass spectrometry).
[0101] Example 3 Synthesis of Elastran
[0102]
[0103] Add methyltetrahydrofuran (1.4L), n-heptane (1L), compound VI-2 (R3=Bn in the compound of formula VI) (135.3g), compound V-1 (125.1g), D-dibenzoyltartaric acid (0.15g) to the reaction kettle, heat to 70-80°C for reaction, complete conversion of raw materials, concentrate, add methyltetrahydrofuran (2L), sodium triacetylborohydride (377.1g), heat to 60-70°C for reaction, after complete conversion of raw materials, cool to 20-30°C, add water to the reaction solution, separate the liquids, extract the aqueous phase with isopropyl acetate, combine the organic phases, and concentrate the organic phases to dryness to obtain a crude product. The crude product is purified by silica gel column to obtain 200.5g of oily product compound of formula VII-2 with a yield of 83.2%.
[0104] Add the compound of formula VII-2 (120 g, 1.0 eq.) and methanol (1.2 L) to the reaction kettle, cool to 0-10°C, add trifluoroacetic acid (63.3 g, 3.0 eq.) dropwise, and after the reaction is completed, concentrate, add water, adjust the pH to 9-10 with an aqueous solution of NaOH, filter, and vacuum dry to obtain the compound of formula VII-3 (91.8 g, yield: 90.4%)
[0105] Add the compound of formula VII-3 (91.7 g), methanol (0.92 L), and 5% Pd / C (2.3 g, 5 wt%) to the hydrogenation reactor, and react at 30-40 psi for 8-10 hours. After the reaction is complete, filter, add HCl aqueous solution (42.3 g) to the mother liquor, concentrate to 5-6 volumes, filter, and vacuum dry to obtain 83.4 g of elastomeric, 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 bottle, 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 the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.
Claims
1. A method for synthesizing elastostat, characterized in that: The synthesis method comprises the steps of: (1) reacting a compound of formula V with a compound of formula VI, and reducing the resulting product with a reducing agent to generate a compound of formula VII, wherein the reducing agent also provides an ethyl group, and the reaction formula is as follows: In the reaction formula, 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.
2. The method for synthesizing elastomeric according to claim 1, characterized in that: In step (1), the compound of formula V reacts with the compound of formula VI at 50-80° C. to generate a Schiff base, and then the Schiff base is reduced by the reducing agent at 40-70° C. and an ethyl group is introduced to obtain a compound of formula VII.
3. The method for synthesizing elastomeric according to claim 2, characterized in that: The reaction to form the Schiff base is carried out in a solvent selected from the following: Toluene, tetrahydrofuran, methyltetrahydrofuran, or a combination thereof, and / or The reaction of reducing the Schiff base and introducing the 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.
4. The method for synthesizing elastomeric according to claim 1, characterized in that: The reducing agent is selected from sodium triacetoxyborohydride.
5. The method for synthesizing elastomeric according to claim 1, characterized in that: The nitrogen protecting group is selected from Boc or Fmoc, and / or The hydroxy protecting group is selected from Bn, Cbz or Ac.
6. The method for synthesizing elastomeric according to claim 1, characterized in that: In step (2), When R3 is H, the compound of formula VII is denitrogenated to obtain elastostat; When R3 is a hydroxyl protecting group, the compound of formula VII is sequentially denitrified with the nitrogen protecting group and the hydroxyl protecting group, or the compound of formula VII is sequentially denitrified with the hydroxyl protecting group and the nitrogen protecting group to obtain elastostrat.
7. The method for synthesizing elastomeric according to claim 1, characterized in that: 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 IV, 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.
8. The method for synthesizing elastostat according to claim 1, characterized in that: 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 or a metal catalyst. The strong base reagent is selected from n-butyl lithium, tert-butyl lithium, metallic lithium, more preferably n-butyl 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.
9. A method for synthesizing a compound of formula V, characterized in that: The synthesis method 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 IV, The reaction formula is as follows: In the reaction formula, R1 is selected from bromine or iodine, and R2 is a nitrogen protecting group.
10. A method for synthesizing elastostat, characterized in that: The synthesis method comprises the following steps: (1) reacting a compound of formula V with a compound of formula VI, and reducing the resulting product with a reducing agent to generate a compound of formula VII, wherein the reducing agent also provides an ethyl group, and the reaction formula is as follows: In the reaction formula, 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 compound of formula V is obtained according to the synthesis method of claim 9.
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