Synthesis method of Fmoc-(S)-2-amino-3-(2apos;-ethyl-4apos;-methoxybiphenyl-4-yl) propionic acid

Abstract

The invention discloses a synthesis method of Fmoc-(S)-2-amino-3-(2 '-ethyl-4'-methoxybiphenyl-4-yl) propionic acid, and relates to the technical field of synthesis of biphenyl alanine containing substituent groups. In order to solve the problem that an amino acid derivative Fmoc-(S)-2-amino-3-(2 '-ethyl-4'-methoxybiphenyl-4-yl) propionic acid cannot be safely, efficiently and massively produced, m-methoxyacetophenone is adopted as a raw material, and the method comprises the following steps: preparing 1-bromine-2-ethyl-4-methoxybenzene through two-step reaction of bromination and reduction; and coupling the (S)-2-amino-3-(2 '-ethyl-4'-methoxybiphenyl-4-yl) propionic acid with Boc-L-4-boric acid phenylalanine, firstly removing Boc protection, and then protecting the (S)-2-amino-3-(2 '-ethyl-4'-methoxybiphenyl-4-yl) propionic acid with Fmoc to obtain Fmoc-(S)-2-amino-3-(2 '-ethyl-4'-methoxybiphenyl-4- The adopted raw materials are cheap and easy to obtain, and large-scale production is facilitated.

Description

Technical Field

[0001] The present invention relates to the technical field of synthesizing substituted biphenylalanine, and specifically to a method for synthesizing Fmoc-(S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propionic acid. Background Art

[0002] (S)-2-Amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propionic acid is an important intermediate of a class of novel hypoglycemic drugs, 11-peptides. The 11-amino acid polypeptide shows high selectivity as a GLP-1 receptor agonist in pharmacological studies, and its in vitro potency is similar to that of natural glucagon-like peptide 1 (GLP-1). The chemical structure of 11-peptides is as follows: 。

[0003] 11-Peptides contain multiple unnatural amino acid fragments, including (S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propionic acid, and there is only one reported synthesis method for it. The Journal Of Medicinal Chemistry 2009, 52(23) 7788–7799 reported a synthesis method for (S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propionic acid. This route involves coupling 2-ethyl-4-methoxyphenylboronic acid with Boc-L-tyrosine methyl ester trifluoromethanesulfonate to obtain protected (S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propionic acid.

[0004] 2-Ethyl-4-methoxyphenylboronic acid can be synthesized through two routes: one is using 2-bromo-5-methoxybenzaldehyde as the raw material, and the other is using m-ethylphenol as the raw material. First, 1-bromo-2-ethyl-4-methoxybenzene is prepared, and then it reacts with n-butyllithium or trimethyl borate to obtain the target product. However, n-butyllithium is a flammable and explosive reagent. The reagent itself will spontaneously combust when exposed to water or moist air, and the reaction process must be strictly anhydrous and anaerobic, and the reaction temperature needs to be below -70ºC; Trimethyl borate is an organoboron compound, usually a colorless liquid with an aromatic odor. It is relatively stable at room temperature, but decomposes into boric acid and methanol when heated or reacted with water. Although trimethyl borate itself is not a flammable and explosive substance, its vapor can form an explosive mixture with air and may burn under high temperature or open flame. At the same time, trimethyl borate is irritating to the eyes, skin and respiratory tract.

[0005] The synthesis of Boc-L-tyrosine methyl ester trifluoromethanesulfonate is prepared by reacting Boc-L-tyrosine methyl ester with trifluoromethanesulfonic anhydride under low-temperature conditions. Trifluoromethanesulfonic anhydride is a compound with a pungent odor and strong corrosiveness. It has strong hygroscopicity and easily absorbs moisture in the air, which will not only reduce the purity and reactivity of the reagent, but may also cause its decomposition, generating corrosive by-products such as trifluoromethanesulfonic acid and sulfuric acid. These by-products will further exacerbate the corrosion of the equipment and reaction system, affecting the accuracy and repeatability of the experiment. Therefore, during storage, it must be placed in a dry and sealed environment and minimize its contact with air.

[0006] After coupling 2-ethyl-4-methoxyphenylboronic acid with Boc-L-tyrosine methyl ester trifluoromethanesulfonate, protected (S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propanoic acid is obtained. After further hydrolysis and deprotection of the tert-butoxycarbonyl (Boc) group, it is then protected with 9-fluorenylmethoxycarbonyl (Fmoc-) to obtain Fmoc-(S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propanoic acid, which is used in the method of solid-phase synthesis to produce 11-peptides.

[0007] Currently, the existing synthetic route uses the flammable and explosive n-butyllithium reagent, and strict control of anhydrous and anaerobic as well as ultra-low temperature (below -70 °C) reaction conditions is required. At the same time, it involves the operation of the highly corrosive Boc-L-tyrosine methyl ester trifluoromethanesulfonate. It not only has extremely high requirements for equipment and processes, but also has significant safety hazards and is difficult to achieve industrial-scale production. The specific synthetic route is described as follows: 。

[0008] To cooperate with preclinical and clinical studies, a large amount of 11-peptides need to be synthesized. Therefore, providing a safe, efficient and suitable synthetic method for large-scale production of the amino acid derivative Fmoc-(S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propanoic acid has become an urgent technical problem to be solved. Summary of the Invention

[0009] To solve the above problems, that is, to solve the problems raised in the above background art, the present invention provides a method for synthesizing Fmoc-(S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propionic acid, which comprises the following steps: S1. Brominating m-methoxyacetophenone with N-bromosuccinimide to obtain 1-(2-bromo-5-methoxyphenyl)ethanone; S2. Reducing 1-(2-bromo-5-methoxyphenyl)ethanone with triethylsilane and trifluoroacetic acid to obtain 1-bromo-2-ethyl-4-methoxybenzene; S3. Coupling 1-bromo-2-ethyl-4-methoxybenzene with Boc-L-4-boronophenylalanine under palladium catalysis to obtain (S)-2-Boc-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propionic acid; S4. Deprotecting (S)-2-Boc-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propionic acid under the action of trifluoroacetic acid to obtain (S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propionic acid trifluoroacetate; S5. Reacting (S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propionic acid trifluoroacetate with 9-fluorenylmethyl-N-succinimidyl carbonate to obtain Fmoc-(S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propionic acid, and the reaction formula is as follows: 。

[0010] A further setting of the present invention is that in the step S1, the molar ratio of m-methoxyacetophenone to N-bromosuccinimide is 1:1-2, preferably 1:1.5.

[0011] A further setting of the present invention is that in the step S2, the molar ratio of 1-(2-bromo-5-methoxyphenyl)ethanone to triethylsilane is 1:2-5, preferably 1:3.

[0012] A further setting of the present invention is that in the step S3, the molar ratio of 1-bromo-2-ethyl-4-methoxybenzene to Boc-L-4-boronophenylalanine is 1:0.9-1.2, preferably 1:1. The palladium catalyst used in the coupling reaction includes but is not limited to one or a combination of more of tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium, dichloro-bis(triphenylphosphine)palladium, and palladium acetate, and preferably tetrakis(triphenylphosphine)palladium(0).

[0013] A further setting of the present invention is that the chemical formula of tris(dibenzylideneacetone)dipalladium is Pd2(dba)3, and the chemical formula of dichloro-bis(triphenylphosphine)palladium is PdCl2(PPh3)2.

[0014] The beneficial technical effects of the present invention are as follows: m-methoxyacetophenone is used as the raw material in the present invention, and 1-bromo-2-ethyl-4-methoxybenzene is prepared through two-step reactions of bromination and reduction. The raw materials are cheap and easily available, and the reaction has high selectivity and good yield; Boc-L-4-boronic acid phenylalanine is used as the coupling raw material, which has stable properties and moderate reaction activity, facilitating large-scale production. After synthesizing the target molecular skeleton by a mature method, the target product is obtained through the transformation of a protecting agent. The post-treatment of the reaction is simple, and qualified products can be obtained by removing impurities through conventional acid-base treatment. The entire synthesis process avoids the harsh conditions for preparing boric acid from 1-bromo-2-ethyl-4-methoxybenzene, filling the technical gap in the synthesis method of such compounds. The raw materials used are easily available, the process route is safe, the operation is convenient, and there is no need for fine operation, deep low-temperature reaction, and flammable and explosive metal organic reagents, enabling large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 The NMR spectrum of Example 1, Fmoc-(S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propanoic acid, is shown.

[0016] Figure 2 The LC-MS mass spectrum of Example 1, Fmoc-(S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propanoic acid, is shown.

[0017] Figure 3 The chiral HPLC spectrum of Example 1, Fmoc-(S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propanoic acid, is shown. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0018] The following refers to the attached Figures 1-3 to describe the preferred embodiments of the present invention. Those skilled in the art should understand that these embodiments are only used to explain the technical principle of the present invention and are not intended to limit the protection scope of the present invention.

[0019] Example 1

[0020] S1. In a 3 L three-necked flask, successively add m-methoxyacetophenone (200.0 g, 1.33 mol) and dichloromethane (1 L), and stir to dissolve it completely. Subsequently, cool the reaction system to 0 °C, and add N-bromosuccinimide (355.0 g, 2 mol) in batches. Stir the reaction at 0 - 10 °C for 2 hours, and then continue to stir overnight at room temperature. After the reaction is completed, filter the reaction solution to remove solid impurities, and then wash the filtrate twice with saturated sodium bicarbonate aqueous solution (500 mL each time). After washing, add anhydrous sodium sulfate to dry the solution. The dried solution is concentrated to dryness to obtain the crude product. Pulp the crude product with a mixed solvent of ethyl acetate and petroleum ether (prepared according to a volume ratio of 1:10, 500 mL), filter and collect the obtained solid, and finally dry it to obtain 253.1 g of 1-(2-bromo-5-methoxyphenyl)ethanone. This substance is a pale yellow solid, and the molar yield is 83%.

[0021] S2. In a 3 L three-necked flask, successively add 1-(2-bromo-5-methoxyphenyl)ethanone (250.0 g, 1.09 mol), Boc-L-4-boronophenylalanine (143.7 g, 0.465 mol), dichloromethane (1 L) and trifluoroacetic acid (500 mL), stir to dissolve, and then add triethylsilane (380 g, 3.27 mol). Heat the reaction solution to 40 - 45 °C and stir for 16 hours. After cooling, concentrate to remove the solvent. The residue is dissolved in ethyl acetate (1 L) and washed four times with saturated sodium bicarbonate aqueous solution (500 mL each time), dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 211.6 g of 1-bromo-2-ethyl-4-methoxybenzene. This substance is an oil, and the molar yield is 90%. It is used directly in the next step without further purification.

[0022] S3. Add 1-bromo-2-ethyl-4-methoxybenzene (100.0 g, 0.465 mol), Boc-L-4-boronophenylalanine (143.7 g, 0.465 mol), anhydrous sodium carbonate (98.6 g, 0.93 mol), dioxane (1 L) and water (150 mL) into a 2-L three-necked flask. After stirring to dissolve most of the solids, displace the air with nitrogen three times. Then add tetrakis(triphenylphosphine)palladium(0) (5 g). After displacing the air in the reaction flask with nitrogen three times again, heat the mixture to 95 - 100 °C and stir for 6 hours. After cooling, filter to remove the solids. Concentrate the filtrate under reduced pressure to remove the organic solvents. Dissolve the residue in water (1 L). Wash it twice with a mixed solvent of ethyl acetate and petroleum ether (prepared by volume ratio 1:10, 500 mL each time). Acidify the aqueous phase with dilute hydrochloric acid to pH = 3, and then extract it three times with ethyl acetate (500 mL each time). Combine the organic phases. Wash it once with water (500 mL each time) and saturated brine (500 mL each time). Dry over anhydrous sodium sulfate and concentrate to dryness. Pulverize the residue with a mixed solvent of ethyl acetate and petroleum ether (prepared by volume ratio 1:2, 500 mL) and filter and dry to obtain 133.0 g of (S)-2-Boc-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propanoic acid. This substance is a pale yellow solid with a molar yield of 72%.

[0023] S4. Add (S)-2-Boc-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propanoic acid (100.0 g, 0.25 mol) and dichloromethane (300 mL) into a 1-L single-necked flask. After stirring to dissolve and cooling to 0 °C, add trifluoroacetic acid (150 mL) in batches. Stir the reaction mixture at 0 - 10 °C for 4 hours. Concentrate the reaction mixture to dryness under reduced pressure to obtain 120.9 g of (S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propanoic acid trifluoroacetate. The molar yield is 100%. This substance is a crude product and is directly used in the next step without further purification.

[0024] S5. In a 2 L beaker, add (S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propionic acid trifluoroacetate (120.9 g, 0.25 mol), acetone (500 mL) and water (500 mL). Stir and adjust the pH value to 7.5 - 8 with 1 N aqueous sodium hydroxide solution. Add 9-fluorenylmethyl-N-succinimidyl carbonate (Fmoc-OSu, 80.0 g, 0.237 mol), and stir the reaction for 5 hours. During the reaction, maintain the pH value at 7.5 - 8 with 1 N aqueous sodium hydroxide solution. After diluting the reaction solution with water (1 L), wash it three times with a mixed solvent of ethyl acetate and petroleum ether (prepared according to a volume ratio of 1:3, 500 mL each time). Acidify the aqueous phase to pH = 3 with dilute hydrochloric acid (1 N), and extract it three times with ethyl acetate (1 L each time). Combine the organic phases, wash them once with water and once with saturated brine successively, dry over anhydrous sodium sulfate, and concentrate to dryness. The residue is triturated with a mixed solvent of ethyl acetate and petroleum ether (prepared according to a volume ratio of 1:2, 500 mL), filtered and dried to obtain 119.3 g of Fmoc-(S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propionic acid. This substance is a white solid, with a molar yield of 91% [calculated from (S)-2-Boc-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propionic acid], and a chiral purity of 100.0%. See the NMR spectrum in Figure 1 , see the LC-MS mass spectrum in Figure 2 , see the chiral HPLC spectrum in Figure 3 .

[0025] NMR spectrum ( 1 H-NMR) data and mass spectrum (LC-MS) data of Fmoc-(S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propionic acid: 1 H-NMR (DMSO- d 6, 400 MHz): δ 12.80 (bs, 1H), 7.90 (m, 2H), 7.82 (d, J = 8.8 Hz, 1H), 7.68 (m, 2H), 7.10 - 7.50 (m, 8H), 7.00 (m, 1H), 6.75 - 6.85 (m, 2H), 4.10 - 4.40 (m, 4H), 3.80 (s, 3H), 3.10 (m, 1H), 2.90 (m, 1H), 2.45 (q, J = 7.2 Hz, 2H), 0.95 (t, J = 7.2 Hz, 3H). The molecular formula is C 33 H 31 NO5, the theoretical relative molecular mass value is 521.22, and the LC-MS measured value is 520.56 [M - H] -, the measured value is close to the theoretical value, indicating that the molecular weight measured in the experiment is basically consistent with the theoretically calculated value, verifying the structural correctness of Fmoc-(S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propanoic acid.

[0026] The condition parameters for chiral analysis of Fmoc-(S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propanoic acid using chiral high performance liquid chromatography (HPLC): Chromatographic column: A Chiralpak IC type chiral chromatographic column was used, with dimensions of 4.6 mm (inner diameter) × 250 mm (length), and the particle size of the packed particles was 5 μm. Chiral chromatographic columns are used to separate compounds with chiral isomers. Different chiral compounds will have different retention behaviors on the chiral column, thus achieving chiral separation and analysis.

[0027] Mobile phase A: An aqueous solution containing 0.025% trifluoroacetic acid. Trifluoroacetic acid is often used as an additive to improve peak shape, adjust the retention behavior of compounds, etc.

[0028] Mobile phase B: An acetonitrile solution containing 0.025% trifluoroacetic acid. Acetonitrile is a commonly used organic solvent in HPLC, and it is mixed with water to form mobile phases with different ratios to achieve sample separation.

[0029] Gradient: In this analysis, an isocratic elution method was adopted, that is, during the entire analysis process, the ratios of mobile phase A and B remained unchanged. Specifically, within 20 minutes from the start to the end, the ratio of mobile phase A was always 40%, and the ratio of mobile phase B was always 60%. Isocratic elution is suitable for cases where the target compound can be well separated under this fixed ratio of mobile phase.

[0030] Flow rate: It was set to 1 mL / min, that is, the volume of the mobile phase passing through the chromatographic column per minute was 1 milliliter. The choice of flow rate will affect the separation efficiency and peak shape. Too fast a flow rate may lead to a decrease in resolution, while too slow may prolong the analysis time.

[0031] Detection: An ultraviolet (UV) detector was used, and the detection wavelength was set to 210 nm. 210 nm is a commonly used detection wavelength. Many organic compounds, especially those containing conjugated structures or aromatic rings, will have strong absorption near this wavelength, thus enabling quantitative or qualitative detection of the compounds.

[0032] Temperature: The operating temperature of the chromatographic column was 20 °C. Temperature affects the diffusion behavior and retention time of molecules, and a stable column temperature helps to obtain chromatographic results with good reproducibility.

[0033] The relative retention time of Fmoc-(S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propanoic acid is 7.978 min, and the relative retention time of the enantiomer Fmoc-(R)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propanoic acid is 9.562 min.

[0034] Example 2

[0035] Differing from Example 1: S3. Add 1-bromo-2-ethyl-4-methoxybenzene (30.0 g, 0.14 mol), Boc-L-4-boronophenylalanine (43.1 g, 0.14 mol), anhydrous sodium carbonate (30.0 g, 0.28 mol), dioxane (300 mL) and water (50 mL) into a 1 L three-necked flask, stir until most of the solids dissolve, displace with nitrogen three times, add tris(dibenzylideneacetone)dipalladium [Pd2(dba)3, 5 g] and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (SPhos, 5 g); displace the reaction flask with nitrogen three times again, then heat to 95 - 100 °C and stir for 6 hours; after cooling, filter to remove the solids, concentrate the filtrate under reduced pressure to remove the organic solvent, dissolve the residue in water (1 L), wash twice with a mixed solvent of ethyl acetate and petroleum ether (prepared by volume ratio of 1:10, 100 mL each time), acidify the aqueous phase with dilute hydrochloric acid to pH = 3, then extract three times with ethyl acetate (200 mL each time), combine the organic phases, wash once with water (200 mL each time) and saturated brine (200 mL each time), dry over anhydrous sodium sulfate, and concentrate to dryness; slurry the residue with a mixed solvent of ethyl acetate and petroleum ether (prepared by volume ratio of 1:2, 200 mL) and filter and dry to obtain 39.2 g of (S)-2-Boc-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propanoic acid. This substance is a pale yellow solid with a molar yield of 70%.

[0036] The molar yields of both steps S4 and S5 are 90%.

[0037] Example 3

[0038] Differing from Example 1: S3. Add 1-bromo-2-ethyl-4-methoxybenzene (30.0 g, 0.14 mol), Boc-L-4-boronophenylalanine (43.1 g, 0.14 mol), anhydrous sodium carbonate (30.0 g, 0.28 mol), dioxane (300 mL) and water (50 mL) into a 1-L three-necked flask. Stir until most of the solids dissolve. Replace the gas with nitrogen three times. Add bis(triphenylphosphine)palladium dichloride [PdCl2(PPh3)2, 5 g] and triphenylphosphine (5 g). Replace the gas in the reaction flask with nitrogen three times again, and then heat to 95 - 100 °C and stir for 6 hours. After cooling, filter to remove the solids. Concentrate the filtrate under reduced pressure to remove the organic solvent. Dissolve the residue in water (1 L), wash twice with a mixed solvent of ethyl acetate and petroleum ether (prepared by volume ratio of 1:10, 100 mL each time). Acidify the aqueous phase with dilute hydrochloric acid to pH = 3, and then extract three times with ethyl acetate (200 mL each time). Combine the organic phases, wash once with water (200 mL each time) and saturated brine (200 mL each time), dry over anhydrous sodium sulfate, and concentrate to dryness. Pulverize the residue with a mixed solvent of ethyl acetate and petroleum ether (prepared by volume ratio of 1:2, 200 mL), filter and dry to obtain 35.3 g of (S)-2-Boc-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propanoic acid. This substance is a pale yellow solid with a molar yield of 63%.

[0039] The molar yields of both steps S4 and S5 are 88%.

[0040] Example 4

[0041] Differing from Example 1 is that: S3. Add 1-bromo-2-ethyl-4-methoxybenzene (30.0 g, 0.14 mol), Boc-L-4-boronophenylalanine (43.1 g, 0.14 mol), anhydrous sodium carbonate (30.0 g, 0.28 mol), dioxane (300 mL) and water (50 mL) into a 1-L three-necked flask. Stir until most of the solids dissolve. Replace the air with nitrogen three times. Add palladium acetate (5 g) and triphenylphosphine (5 g). Replace the air in the reaction flask with nitrogen three more times, then heat to 95 - 100 °C and stir for 6 hours. After cooling, filter to remove the solids. Concentrate the filtrate under reduced pressure to remove the organic solvents. Dissolve the residue in water (1 L), wash it twice with a mixed solvent of ethyl acetate and petroleum ether (prepared at a volume ratio of 1:10, 100 mL each time). Acidify the aqueous phase with dilute hydrochloric acid to pH = 3, then extract it three times with ethyl acetate (200 mL each time). Combine the organic phases, wash them once with water (200 mL each time) and saturated brine (200 mL each time), dry over anhydrous sodium sulfate, and concentrate to dryness. Pulverize the residue with a mixed solvent of ethyl acetate and petroleum ether (prepared at a volume ratio of 1:2, 200 mL) and filter and dry to obtain 30.7 g of (S)-2-Boc-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propanoic acid. This substance is a pale yellow solid with a molar yield of 55%.

[0042] The molar yields of both steps S4 and S5 are 87%.

[0043] Although the present invention has been described with reference to the preferred embodiments, various modifications can be made to it without departing from the scope of the present invention, and components therein can be replaced with equivalents. In particular, as long as there is no structural conflict, the technical features mentioned in each embodiment can be combined in any way. The present invention is not limited to the specific embodiments disclosed herein, but includes all technical solutions falling within the scope of the claims.

[0044] In the description of the present invention, the terms such as "center", "upper", "lower", "left", "right", "vertical", "horizontal", "inner", "outer", etc., which indicate directions or positional relationships, are based on the directions or positional relationships shown in the drawings. This is only for convenience of description, rather than indicating or implying that the device or element must have a specific orientation, be constructed and operated in a specific orientation, and thus cannot be construed as a limitation of the present invention. In addition, the terms "first", "second", "third" are only used for descriptive purposes and cannot be construed as indicating or implying relative importance.

[0045] In addition, it should be noted that in the description of the present invention, unless otherwise clearly specified and defined, the terms "installed", "connected", and "coupled" should be understood in a broad sense. For example, it may be a fixed connection, a detachable connection, or an integral connection; it may be a mechanical connection or an electrical connection; it may be directly connected or indirectly connected through an intermediate medium, and it may be the communication inside two elements. For those skilled in the art, the specific meanings of the above terms in the present invention can be understood according to specific circumstances.

[0046] The term "comprising" or any other similar term is intended to cover non-exclusive inclusion, so that a process, article, or apparatus / device comprising a series of elements includes not only those elements but also other elements not expressly listed, or also includes elements inherent in these processes, articles, or apparatus / device.

[0047] So far, the technical solution of the present invention has been described in conjunction with the preferred embodiments shown in the drawings. However, it is easy for those skilled in the art to understand that the protection scope of the present invention is obviously not limited to these specific embodiments. Without departing from the principle of the present invention, those skilled in the art can make equivalent changes or substitutions to the relevant technical features, and the technical solutions after these changes or substitutions will fall within the protection scope of the present invention.

Claims

1. A method for synthesizing Fmoc-(S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propionic acid, characterized in that: It includes the following steps: S1. Brominate m-methoxyacetophenone with N-bromosuccinimide to obtain 1-(2-bromo-5-methoxyphenyl)ethanone; S2. Reduce 1-(2-bromo-5-methoxyphenyl)ethanone with triethylsilane and trifluoroacetic acid to obtain 1-bromo-2-ethyl-4-methoxybenzene; S3. Couple 1-bromo-2-ethyl-4-methoxybenzene with Boc-L-4-boronophenylalanine under palladium catalysis to obtain (S)-2-Boc-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propanoic acid; S4. Deprotect (S)-2-Boc-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propanoic acid under the action of trifluoroacetic acid to obtain (S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propanoic acid trifluoroacetate; S5. React (S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propanoic acid trifluoroacetate with 9-fluorenylmethyl-N-succinimidyl carbonate to obtain Fmoc-(S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propanoic acid. The reaction formula is as follows: 。 2. The synthesis method of Fmoc-(S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propanoic acid according to claim 1, characterized in that: In the above S1, the molar ratio of m-methoxyacetophenone to N-bromosuccinimide is 1:1-2.

3. The synthesis method of Fmoc-(S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl) propionic acid according to claim 1, characterized in that: In the above S2, the molar ratio of 1-(2-bromo-5-methoxyphenyl)ethanone to triethylsilane is 1:2-5.

4. The synthesis method of Fmoc-(S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propanoic acid according to claim 1, characterized in that: In the above S3, the molar ratio of 1-bromo-2-ethyl-4-methoxybenzene to Boc-L-4-boronophenylalanine is 1:0.9-1.

2. The palladium catalyst used in the coupling reaction includes but is not limited to one or a combination of more than one of tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium, bis(triphenylphosphine)palladium chloride, and palladium acetate.

5. The synthesis method of Fmoc-(S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl) propionic acid according to claim 4, characterized in that: The chemical formula of the tris(dibenzylideneacetone)dipalladium is Pd2(dba)3, and the chemical formula of the dichlorobis(triphenylphosphine)palladium is PdCl2(PPh3). 2。

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