A method for synthesizing Fmoc-(S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propionic acid

Abstract

The present invention discloses a method for synthesizing Fmoc-(S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propionic acid, relating to the technical field of synthesizing substituted biphenylalanine. The method aims to solve the problem that the amino acid derivative Fmoc-(S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propionic acid cannot be produced safely, efficiently, and on a large scale. The method uses m-methoxyacetophenone as a raw material, comprising the following steps: preparing 1-bromo-2-ethyl-4-methoxybenzene through a two-step bromination and reduction reaction, coupling with Boc-L-4-boronic acid phenylalanine, first removing the Boc protection and then protecting with Fmoc to obtain Fmoc-(S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propionic acid. The raw materials used in the method are inexpensive and readily available, facilitating large-scale production.

Description

Technical Field

[0001] The present invention relates to the technical field of synthesizing biphenylalanine containing a substituent, in particular 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 in a new class of glucose-lowering drugs called 11-peptides. This 11-amino acid peptide has been shown in pharmacological studies to be a highly selective GLP-1 receptor agonist, with in vitro potency similar to that of natural glucagon-like peptide 1 (GLP-1). The chemical structure of 11-peptides is as follows:

[0003] .

[0004] 11-peptides contain multiple unnatural amino acid fragments, including (S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propionic acid, the synthesis of which has only been reported in one method. The Journal of Medicinal Chemistry 2009, 52 (23) 7788–7799 reported a method for synthesizing (S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propionic acid. This route involved 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.

[0005] 2-Ethyl-4-methoxyphenylboronic acid can be synthesized via two routes: one using 2-bromo-5-methoxybenzaldehyde or m-ethylphenol as the starting materials. 1-Bromo-2-ethyl-4-methoxybenzene is then produced by reacting it with n-butyllithium or trimethyl borate to yield the target product. However, n-butyllithium is a flammable and explosive reagent that spontaneously ignites in contact with water or moist air. Therefore, the reaction must be conducted in a strictly anhydrous and oxygen-free environment, and the reaction temperature must be below -70°C. Trimethyl borate is an organoboron compound, typically a colorless liquid with an aromatic odor. While relatively stable at room temperature, it decomposes to form boric acid and methanol upon reaction with water or at elevated temperatures. While trimethyl borate itself is not flammable or explosive, its vapor can form explosive mixtures with air and may ignite at elevated temperatures or under open flames. Furthermore, trimethyl borate is irritating to the eyes, skin, and respiratory tract.

[0006] Boc-L-tyrosine methyl ester trifluoromethanesulfonate is synthesized by reacting Boc-L-tyrosine methyl ester with trifluoromethanesulfonic anhydride at low temperatures. Trifluoromethanesulfonic anhydride is a highly corrosive compound with a pungent odor. It is highly hygroscopic and readily absorbs moisture from the air. This not only reduces the purity and reactivity of the reagent but can also cause its decomposition, producing corrosive byproducts such as trifluoromethanesulfonic acid and sulfuric acid. These byproducts can further corrode the equipment and reaction system, affecting the accuracy and reproducibility of the experiment. Therefore, during storage, it must be kept in a dry, sealed environment, and its exposure to air must be minimized.

[0007] 2-Ethyl-4-methoxyphenylboronic acid was coupled with Boc-L-tyrosine methyl ester trifluoromethanesulfonate to obtain protected (S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propionic acid, which was further hydrolyzed and deprotected with the tert-butyloxycarbonyl (Boc) group, and then protected with the fluorenylmethyloxycarbonyl (Fmoc-) group to obtain Fmoc-(S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propionic acid, which was used for solid-phase synthesis to produce 11-peptides.

[0008] Currently, the existing synthesis route uses the flammable and explosive n-butyl lithium reagent, requires strict control of anhydrous and oxygen-free reaction conditions and ultra-low temperature (below -70°C), and also involves the operation of highly corrosive Boc-L-tyrosine methyl ester trifluoromethanesulfonate. This not only places extremely high demands on equipment and processes, but also poses significant safety risks, making it difficult to achieve industrial scale-up production. The specific synthesis route is described as follows:

[0009] .

[0010] To facilitate preclinical and clinical research, it is necessary to synthesize a large amount of 11-peptides. Therefore, providing a safe, efficient and suitable synthesis method for large-scale production of the amino acid derivative Fmoc-(S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propionic acid has become a technical problem that needs to be solved urgently. Summary of the Invention

[0011] In order to solve the above problems, that is, to solve the problems raised by the above background technology, the present invention proposes 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-boronic acid phenylalanine under palladium catalysis to obtain (S)-2-Bo c-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, the reaction formula is as follows:

[0012] .

[0013] The present invention is further configured as follows: in S1, the molar ratio of m-methoxyacetophenone to N-bromosuccinimide is 1:1-2, preferably 1:1.5.

[0014] The present invention is further configured as follows: in S2, the molar ratio of 1-(2-bromo-5-methoxyphenyl)ethanone to triethylsilane is 1:2-5, preferably 1:3.

[0015] The present invention is further configured as follows: in said S3, the molar ratio of 1-bromo-2-ethyl-4-methoxybenzene to Boc-L-4-boronic acid phenylalanine is 1:0.9-1.2, preferably 1:1, and the palladium catalyst used in the coupling reaction includes but is not limited to one or more combinations of tetrakis(triphenylphosphine)palladium (0), tris(dibenzylideneacetone)dipalladium, bis(triphenylphosphine)palladium chloride and palladium acetate, preferably tetrakis(triphenylphosphine)palladium (0).

[0016] The present invention is further configured as follows: the chemical formula of the tris(dibenzylideneacetone)dipalladium is Pd2(dba)3, and the chemical formula of the bis(triphenylphosphine)palladium chloride is PdCl2(PPh3)2.

[0017] The beneficial technical effects of the present invention are as follows: the present invention uses m-methoxyacetophenone as a raw material, and obtains 1-bromo-2-ethyl-4-methoxybenzene through a two-step reaction of bromination and reduction. The raw materials are cheap and easy to obtain, and the reaction selectivity is high and the yield is good. Boc-L-4-boronic acid phenylalanine is used as a coupling raw material, which has stable properties and moderate reaction activity, and is conducive to scale-up production. After synthesizing the target molecular skeleton using a mature method, the target product is obtained by conversion with a protective agent. The post-reaction treatment is simple, and the qualified product can be removed by conventional acid and alkali 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 this type of compound. The raw materials used are easy to obtain, the process route is safe, the operation is convenient, and there is no need for delicate operations, deep low-temperature reactions, and flammable and explosive metal organic reagents, so large-scale production can be achieved. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 The NMR spectrum of Fmoc-(S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propanoic acid from Example 1 is shown.

[0019] Figure 2 The LC-MS mass spectrum of Fmoc-(S)-2-amino-3-(2′-ethyl-4′-methoxybiphenyl-4-yl)propanoic acid of Example 1 is shown.

[0020] 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

[0021] Please refer to the attached Figure 1-3 It should be understood by those skilled in the art that these embodiments are only used to explain the technical principles of the present invention and are not intended to limit the scope of protection of the present invention.

[0022] Example 1

[0023] S1. Add m-methoxyacetophenone (200.0 g, 1.33 mol) and dichloromethane (1 L) to a 3 L three-necked flask in sequence and stir to fully dissolve. Then, cool the reaction system to 0°C and add N-bromosuccinimide (355.0 g, 2 mol) in batches. Stir and react at 0-10°C for 2 hours, then continue stirring at room temperature overnight. After the reaction, filter the reaction solution to remove solid impurities, and then wash the filtrate twice with saturated sodium bicarbonate aqueous solution (500 mL each). After washing, add anhydrous sodium sulfate to dry the solution. The dried solution is concentrated to dryness to obtain a crude product. Slurry the crude product with a mixed solvent of ethyl acetate and petroleum ether (prepared in a volume ratio of 1:10, 500 mL). Filter and collect the resulting solid, and finally dry it to obtain 253.1 g of 1-(2-bromo-5-methoxyphenyl)ethanone as a light yellow solid with a molar yield of 83%.

[0024] S2. To a 3 L three-necked flask, add 1-(2-bromo-5-methoxyphenyl)ethanone (250.0 g, 1.09 mol), Boc-L-4-boronic acid phenylalanine (143.7 g, 0.465 mol), dichloromethane (1 L), and trifluoroacetic acid (500 mL) in sequence. Stir to dissolve, then add triethylsilane (380 g, 3.27 mol). Heat the reaction mixture to 40-45°C and stir for 16 hours. After cooling, concentrate to remove the solvent. Dissolve the residue in ethyl acetate (1 L) and wash four times with saturated sodium bicarbonate (500 mL each time). Dry over anhydrous sodium sulfate and concentrate to dryness to yield 211.6 g of 1-bromo-2-ethyl-4-methoxybenzene as an oil with a molar yield of 90%. Use the mixture directly in the next reaction without further purification.

[0025] S3. Add 1-bromo-2-ethyl-4-methoxybenzene (100.0 g, 0.465 mol), Boc-L-4-boronic acid phenylalanine (143.7 g, 0.465 mol), anhydrous sodium carbonate (98.6 g, 0.93 mol), dioxane (1 L) and water (150 mL) to a 2 L three-necked flask. Stir to dissolve most of the solids, replace with nitrogen three times, add tetrakis(triphenylphosphine)palladium (0) (5 g), replace the reaction flask with nitrogen three times, heat to 95-100 ° C, stir and react for 6 hours; after cooling, filter to remove the solids, concentrate the filtrate under reduced pressure to remove the organic solvent, and add water (1 L) to dissolve the residue; acetic acid The product was washed twice with a mixed solvent of ethyl acetate and petroleum ether (prepared in a volume ratio of 1:10, 500 mL each time), the aqueous phase was acidified to pH = 3 with dilute hydrochloric acid, and then extracted three times with ethyl acetate (500 mL each time), and the organic phases were combined; the product was washed once with water (500 mL each time) and saturated brine (500 mL each time), dried over anhydrous sodium sulfate, and concentrated to dryness; the residue was slurried with a mixed solvent of ethyl acetate and petroleum ether (prepared in a volume ratio of 1:2, 500 mL), filtered and dried to obtain 133.0 g of (S)-2-Boc-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propanoic acid as a light yellow solid with a molar yield of 72%.

[0026] S4. Add (S)-2-Boc-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propionic acid (100.0 g, 0.25 mol) and dichloromethane (300 mL) to a 1 L single-necked flask, stir and dissolve, then cool to 0°C. Add trifluoroacetic acid (150 mL) in batches, and stir the reaction solution at 0-10°C for 4 hours. Concentrate the reaction solution under reduced pressure to dryness to obtain 120.9 g of (S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propionic acid trifluoroacetate with a molar yield of 100%. This crude product was used directly in the next reaction without further purification.

[0027] S5. 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) to a 2 L beaker, stir and adjust the pH to 7.5-8 with 1 N sodium hydroxide aqueous solution, add 9-fluorenylmethyl-N-succinimidyl carbonate (Fmoc-OSu, 80.0 g, 0.237 mol), stir and react for 5 hours. During the reaction, the pH is maintained at 7.5-8 with 1 N sodium hydroxide aqueous solution; dilute the reaction solution with water (1 L) and add a mixed solvent of ethyl acetate and petroleum ether (prepared in a volume ratio of 1:3, 500 mL each time); The mixture was washed three times with 1 mL of ethyl acetate (1 L each); the aqueous phase was acidified to pH 3 with dilute hydrochloric acid (1 N) and extracted three times with ethyl acetate (1 L each). The organic phases were combined, washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was slurried with a mixed solvent of ethyl acetate and petroleum ether (1:2 by volume, 500 mL), filtered, and dried to obtain 119.3 g of Fmoc-(S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propionic acid as 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 for details. Figure 1 , LC-MS mass spectrum see Figure 2 , chiral HPLC spectrum see Figure 3 .

[0028] The NMR spectrum of Fmoc-(S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propionic acid ( 1 H-NMR) data and mass spectrometry (LC-MS) data:

[0029] 1 H-NMR (DMSO- d 6, 400MHz): δ12.80 (bs, 1H), 7.90 (m, 2H), 7.82 (d, J =8.8Hz, 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 =7.2Hz, 2H), 0.95(t, J =7.2Hz, 3H). The molecular formula is C 33 H 31 NO5, the theoretical relative molecular mass is 521.22, and the LC-MS determination value is 520.56 [MH]- The measured value is close to the theoretical value, indicating that the experimentally measured molecular weight is basically consistent with the theoretically calculated value, verifying the structural correctness of Fmoc-(S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propionic acid.

[0030] Chiral high performance liquid chromatography (HPLC) parameters for chiral analysis of Fmoc-(S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propanoic acid:

[0031] Chromatographic column: A Chiralpak IC chiral column was used, measuring 4.6 mm (inner diameter) x 250 mm (length), with 5 μm particles. Chiral columns are used to separate compounds with chiral isomers. Different chiral compounds exhibit different retention behaviors on chiral columns, enabling chiral separation and analysis.

[0032] Mobile phase A is an aqueous solution containing 0.025% trifluoroacetic acid. Trifluoroacetic acid is often used as an additive to improve peak shape and adjust compound retention.

[0033] Mobile phase B: Acetonitrile solution containing 0.025% trifluoroacetic acid. Acetonitrile is a commonly used organic solvent in HPLC and is mixed with water to form mobile phases in varying proportions to achieve sample separation.

[0034] Gradient: In this analysis, an isocratic elution method was used, meaning the ratio of mobile phases A and B remained constant throughout the analysis. Specifically, from the beginning to the end of the 20-minute run, mobile phase A remained at 40% and mobile phase B remained at 60%. Isocratic elution is suitable when target compounds can be well separated using this fixed ratio of mobile phases.

[0035] Flow rate: Set to 1 mL / min, meaning 1 mL of mobile phase passes through the column every minute. The flow rate affects separation efficiency and peak shape. A flow rate that is too fast may result in reduced resolution, while a flow rate that is too slow may extend analysis time.

[0036] Detection: An ultraviolet (UV) detector was used, with the detection wavelength set at 210 nm. 210 nm is a commonly used detection wavelength. Many organic compounds, especially those containing conjugated structures or aromatic rings, have strong absorption near this wavelength, enabling quantitative or qualitative detection of the compounds.

[0037] Temperature: The operating temperature of the chromatographic column is 20°C. Temperature affects the diffusion behavior and retention time of molecules. A stable column temperature helps to obtain reproducible chromatographic results.

[0038] The relative retention time of Fmoc-(S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propionic acid was 7.978 min, and the relative retention time of the enantiomer Fmoc-(R)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propionic acid was 9.562 min.

[0039] Example 2

[0040] The difference from Example 1 is that:

[0041] S3. Add 1-bromo-2-ethyl-4-methoxybenzene (30.0 g, 0.14 mol), Boc-L-4-boronic acid phenylalanine (43.1 g, 0.14 mol), anhydrous sodium carbonate (30.0 g, 0.28 mol), dioxane (300 mL) and water (50 mL) to a 1 L three-necked flask, stir until most of the solid is dissolved, replace the atmosphere with nitrogen three times, add tris(dibenzylideneacetone)dipalladium [Pd2(dba)3, 5 g] and 2-dicyclohexylphosphine-2', 6'-dimethoxybiphenyl (SPhos, 5 g); replace the atmosphere with nitrogen three times, then heat to 95-100 ° C and stir to react for 6 hours; after cooling, filter to remove the solid, and concentrate the filtrate under reduced pressure to remove the solid. The organic solvent was removed, and the residue was dissolved in water (1 L). The residue was washed twice with a mixed solvent of ethyl acetate and petroleum ether (prepared in a volume ratio of 1:10, 100 mL each time). The aqueous phase was acidified to pH = 3 with dilute hydrochloric acid, and then extracted three times with ethyl acetate (200 mL each time). The organic phases were combined, washed once with water (200 mL each time) and saturated brine (200 mL each time), dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was slurried with a mixed solvent of ethyl acetate and petroleum ether (prepared in a volume ratio of 1:2, 200 mL), filtered and dried to obtain 39.2 g of (S)-2-Boc-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propionic acid as a light yellow solid with a molar yield of 70%.

[0042] The molar yields of both steps S4 and S5 were 90%.

[0043] Example 3

[0044] The difference from Example 1 is that:

[0045] S3. Add 1-bromo-2-ethyl-4-methoxybenzene (30.0 g, 0.14 mol), Boc-L-4-boronic acid phenylalanine (43.1 g, 0.14 mol), anhydrous sodium carbonate (30.0 g, 0.28 mol), dioxane (300 mL) and water (50 mL) to a 1 L three-necked flask, stir until most of the solid is dissolved, replace the atmosphere with nitrogen three times, add bis(triphenylphosphine)palladium chloride [PdCl2(PPh3)2, 5 g] and triphenylphosphine (5 g); replace the atmosphere with nitrogen three times again, then heat to 95-100 ° C and stir to react for 6 hours; after cooling, filter to remove the solid, concentrate the filtrate under reduced pressure to remove the organic solvent, and add water to the residue ( The mixture was dissolved in 1L of ethyl acetate and petroleum ether (prepared in a volume ratio of 1:10, 100 mL each time), and the aqueous phase was acidified to pH = 3 with dilute hydrochloric acid and extracted three times with ethyl acetate (200 mL each time). The organic phases were combined and washed once with water (200 mL each time) and saturated brine (200 mL each time), dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was slurried with a mixed solvent of ethyl acetate and petroleum ether (prepared in a volume ratio of 1:2, 200 mL), filtered and dried to obtain 35.3 g of (S)-2-Boc-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propanoic acid as a light yellow solid with a molar yield of 63%.

[0046] The molar yields of both steps S4 and S5 were 88%.

[0047] Example 4

[0048] The difference from Example 1 is that:

[0049] S3. Add 1-bromo-2-ethyl-4-methoxybenzene (30.0 g, 0.14 mol), Boc-L-4-boronic acid phenylalanine (43.1 g, 0.14 mol), anhydrous sodium carbonate (30.0 g, 0.28 mol), dioxane (300 mL) and water (50 mL) to a 1 L three-necked flask, stir until most of the solid is dissolved, replace with nitrogen three times, add palladium acetate (5 g) and triphenylphosphine (5 g); replace the reaction flask with nitrogen three times, then heat to 95-100 ° C and stir to react for 6 hours; after cooling, filter to remove the solid, concentrate the filtrate under reduced pressure to remove the organic solvent, add water (1 L) to dissolve the residue, and then use acetic acid to remove the residue. The product was washed twice with a mixed solvent of ethyl acetate and petroleum ether (prepared in a volume ratio of 1:10, 100 mL each time), the aqueous phase was acidified to pH = 3 with dilute hydrochloric acid, and then extracted three times with ethyl acetate (200 mL each time). The organic phases were combined, washed once with water (200 mL each time) and saturated brine (200 mL each time), dried over anhydrous sodium sulfate, and concentrated to dryness; the residue was slurried with a mixed solvent of ethyl acetate and petroleum ether (prepared in a volume ratio of 1:2, 200 mL), filtered and dried to obtain 30.7 g of (S)-2-Boc-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propanoic acid as a light yellow solid with a molar yield of 55%.

[0050] The molar yields of both steps S4 and S5 were 87%.

[0051] Although the present invention has been described with reference to preferred embodiments, various modifications may be made thereto and equivalent components may be substituted without departing from the scope of the present invention. In particular, the various technical features described in the various embodiments may be combined in any manner as long as no structural conflicts exist. The present invention is not limited to the specific embodiments disclosed herein, but encompasses all technical solutions within the scope of the claims.

[0052] In the description of the present invention, terms such as "center," "upper," "lower," "left," "right," "vertical," "horizontal," "inner," and "outer" indicating directions or positional relationships are based on the directions or positional relationships shown in the accompanying drawings. These are intended solely for ease of description and are not intended to indicate or imply that the device or component described must have, be constructed, or operate in a specific orientation. Therefore, they should not be construed as limitations on the present invention. Furthermore, the terms "first," "second," and "third" are used for descriptive purposes only and are not intended to indicate or imply relative importance.

[0053] Furthermore, it should be noted that, in the description of the present invention, unless otherwise expressly specified or limited, the terms "mounted," "connected," and "connected" should be understood in a broad sense. For example, they may refer to fixed connections, detachable connections, or integral connections; mechanical connections or electrical connections; direct connections or indirect connections through an intermediate medium; and internal communication between two components. Those skilled in the art will understand the specific meanings of the above terms in the present invention based on specific circumstances.

[0054] The term "comprise" or any other similar term is intended to cover non-exclusive inclusion, such that a process, article, or apparatus / device that comprises a list of elements includes not only those elements but also other elements not expressly listed or inherent to such process, article, or apparatus / device.

[0055] Thus far, the technical solutions of the present invention have been described in conjunction with the preferred embodiments shown in the accompanying drawings. However, it will be readily understood by those skilled in the art that the scope of protection of the present invention is obviously not limited to these specific embodiments. Without departing from the principles of the present invention, those skilled in the art may make equivalent changes or substitutions to the relevant technical features, and the technical solutions after such changes or substitutions will fall within the scope of protection 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: The following steps are involved: 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-boronic acid phenylalanine 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. (S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propionic acid trifluoroacetate is reacted with 9-fluorenylmethyl-N-succinimidyl carbonate to obtain Fmoc-(S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propionic acid. The reaction formula is as follows:

2. The method for synthesizing Fmoc-(S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propionic acid according to claim 1, wherein: In the S1, the molar ratio of m-methoxyacetophenone to N-bromosuccinimide is 1:1-2.

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

4. The method for synthesizing Fmoc-(S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propionic acid according to claim 1, wherein: In S3, the molar ratio of 1-bromo-2-ethyl-4-methoxybenzene to Boc-L-4-boronic acid phenylalanine is 1:0.9-1.2, and the palladium catalyst used in the coupling reaction is one or more combinations of tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium, bis(triphenylphosphine)palladium chloride and palladium acetate.

5. The method for synthesizing Fmoc-(S)-2-amino-3-(2'-ethyl-4'-methoxybiphenyl-4-yl)propionic acid according to claim 4, wherein: The chemical formula of the tris(dibenzylideneacetone)dipalladium is Pd2(dba)3, and the chemical formula of the bis(triphenylphosphine)palladium chloride is PdCl2(PPh3)2.

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