Preparation method of phenylpropionate derivative

Abstract

The invention discloses a preparation method of a phenylpropionate derivative, which comprises the following steps: dissolving a compound 1 in a first organic solvent, dropwise adding a catalyst while stirring, carrying out heating reflux reaction completely, and carrying out post-treatment to obtain a compound 2; dissolving the compound 2 in a second organic solvent, adding an alkylating reagent and alkali, carrying out room temperature or heating reflux until the reaction is complete, and carrying out post-treatment to obtain a compound 3; compared with the prior art, the synthetic raw materials are easy to obtain, the preparation route is novel, the reaction operation and post-treatment are simple, the reaction conditions are mild, the reaction time is short, and energy conservation is facilitated. The synthesis steps are convenient, the product quality is good, the yield is high, and the industrial production value is remarkable.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis and preparation technology, and specifically relates to a method for preparing a phenylpropionate derivative. Background Technology

[0002] Phenylacetate derivatives are important intermediates in the synthesis of pharmaceutical products and can be widely used in the synthesis of nonsteroidal anti-inflammatory drugs, antithrombotic / cardiovascular drugs, antibacterial synergists, and antitumor drugs. Existing methods for preparing phenylpropionate derivatives have low yields, complex synthesis processes, and unstable yields. There is a need to invent a new preparation method to overcome the shortcomings of existing technologies, aiming to achieve simple synthesis steps, readily available raw materials, and an economical synthesis process, thus laying a good technical foundation for future industrial production.

[0003] In existing technologies, there are three main synthetic routes for phenylpropionate derivatives: The literature (CCS Chemistry, 2022, Vol. 4, 1199-1207) describes the preparation of phenylpropionate derivatives from benzaldehyde derivatives and diethylphosphonoacetate under strongly alkaline conditions (Wittig-Horner reaction, route shown below). This intermediate is then hydrogenated and reduced under transition metal catalysis to obtain the phenylpropionate derivative. In this route, the first step requires a strong base such as sodium hydride, making post-processing difficult. The second step, hydrogenation and reduction, requires expensive transition metal catalysis such as palladium or rhodium, causing environmental pollution and posing safety risks in industrial production.

[0004]

[0005] The literature (ChemCatChem, 2025, Vol. 17, e202402000; Journal of Catalysis, 2024, Vol. 432, 115406; European Journal of Organic Chemistry, 2020, Vol. 8, 932-936; Chemical Communications, 2015, Vol. 51, 12574-12577) uses styrene derivatives, carbon monoxide, and methanol as raw materials to synthesize phenyl acrylate derivatives in one step. Although the synthetic route is relatively short, this reaction is prone to introducing isomers, resulting in unstable yields (5%-85%). It requires long-term high-temperature and high-pressure reactions (3MPa, 100-130 degrees Celsius, 12-16h) and the use of palladium or nickel catalysts, which is environmentally unfriendly and not conducive to industrial production.

[0006]

[0007] Lingen et al. synthesized phenylpropionate esters and their derivatives in one step using substituted phenylpropyne, carbon dioxide, and methanol. However, the raw materials were not readily available, and copper and palladium metal catalysis were required for hydrogenation. The reaction yield was around 80%, and further improvements are needed.

[0008] Summary of the Invention

[0009] The purpose of this invention is to provide a method for preparing phenylpropionate derivatives.

[0010] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0011] This invention provides a method for preparing a phenylpropionate derivative, comprising the following steps:

[0012]

[0013] Wherein, R1 is selected from hydrogen, halogens (fluorine, chlorine, bromine, iodine); R2 is selected from C1 to C30 alkyl groups (methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl); R3 is selected from C1 to C30 alkyl groups (methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl).

[0014] Compound 1 was dissolved in a first organic solvent, and a catalyst was added dropwise with stirring. The molar ratio of the catalyst to compound 1 was 0.05 to 1:1. The reaction was carried out under reflux until complete, and compound 2 was obtained after post-treatment.

[0015] The first organic solvent is selected from monohydric alcohols;

[0016] The catalyst is selected from protic acids;

[0017] The protic acid is selected from sulfuric acid, hydrochloric acid, p-toluenesulfonic acid, and trifluoroacetic acid;

[0018] Compound 2 was dissolved in a second organic solvent, and an alkylating agent and a base were added. The molar ratio of the alkylating agent to compound 2 was 1 to 5:1, and the molar ratio of the base to compound 2 was 1 to 5:1. The reaction was carried out at room temperature or under reflux until the reaction was complete, and compound 3 was obtained after post-treatment.

[0019] The alkylating agent is selected from haloalkanes and ester compounds; the haloalkanes are selected from iodomethane, iodoethane, bromomethane, etc.; the ester compounds are selected from dimethyl sulfate, methyl p-toluenesulfonate, dimethyl carbonate, etc.

[0020] The alkali is selected from inorganic metal alkalis.

[0021] The molar ratio of the catalyst to compound 1 is selected from 0.05:1, 0.1:1, 0.2:1, 0.3:1, and 0.4:1.

[0022] The monohydric alcohol is selected from methanol, ethanol, isopropanol, n-propanol, n-butanol, and tert-butanol.

[0023] The second organic solvent is selected from acetone, diethyl ether, DMF, toluene, isopropyl ether, xylene, chloroform, carbon tetrachloride, dichloromethane, tetrahydrofuran, dioxane, etc.

[0024] The inorganic metal alkali is selected from potassium carbonate, cesium carbonate, sodium carbonate, lithium carbonate, etc.

[0025] The molar ratio of the alkylating agent to compound 2 is 2:1.

[0026] The molar ratio of the base to compound 2 is 2.5:1.

[0027] Compound 1 is selected from one of the following structures:

[0028]

[0029] Compound 2 is selected from one of the following structures:

[0030]

[0031] Compound 3 is selected from one of the following structures:

[0032]

[0033] By adopting the above technical solution, the present invention has the following advantages and beneficial effects:

[0034] This invention provides a method for preparing phenylpropionate derivatives. Starting with commercially available synthetic raw materials, the target compound is prepared through a two-step reaction involving ring-opening and substitution. The preparation route is novel, and the reaction operation is simple. The reaction conditions are relatively mild, and the reaction can be carried out at room temperature and pressure, eliminating the need for the high temperature and high pressure conditions required in existing technologies. Furthermore, the reaction time is short, which is beneficial for energy conservation. No transition metal catalysts are required during the reaction, post-reaction processing is simple, the reaction is relatively environmentally friendly, the product quality is good, the yield is high, and the requirements for equipment are low, demonstrating significant industrial production value. Attached Figure Description

[0035] Figure 1 This is the hydrogen spectrum of methyl 3-(2-methoxyphenyl)propionate. Detailed Implementation

[0036] To more clearly illustrate the present invention, the following description, in conjunction with preferred embodiments, further clarifies the invention. Those skilled in the art should understand that the specific descriptions below are illustrative rather than restrictive, and should not be construed as limiting the scope of protection of the present invention.

[0037] Example 1

[0038]

[0039] Dihydrocoumarin, i.e., compound 11 (6.7 mmol, 1.0 g), was added to a three-necked flask, followed by 30 mL of methanol dried over a molecular sieve. Concentrated sulfuric acid (1.34 mmol, 0.13 g, 0.07 mL) was added dropwise with stirring. After the addition was complete, the mixture was heated to reflux. The reaction was stopped after TLC monitoring showed complete reaction. Methanol was removed by vacuum distillation, and 50 mL of ethyl acetate was added. The organic phase was washed with water, saturated sodium bicarbonate solution, and saturated sodium chloride solution, respectively. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and dried to give 1.20 g of compound 21, i.e., methyl 3-(2-hydroxyphenyl)propionate, in 98.5% yield. The structure was confirmed by NMR.

[0040]

[0041] Methyl 3-(2-hydroxyphenyl)propionate, i.e., compound 21 (0.01 mol, 1.8 g), was added to a three-necked flask, along with 60 mL of diethyl ether dried over a molecular sieve, dimethyl sulfate (0.02 mol, 2.52 g), and potassium carbonate (0.025 mol, 3.45 g). The mixture was heated to reflux and the reaction was stopped after complete TLC monitoring. The mixture was filtered, the solvent was removed under reduced pressure, and 100 mL of ethyl acetate was added. The organic phase was washed with water, saturated sodium bicarbonate solution, and saturated sodium chloride solution, respectively. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 15:1) to give 1.76 g of compound 31, i.e., methyl 3-(2-methoxyphenyl)propionate, in 90.8% yield. Figure 1 This is the hydrogen spectrum of methyl 3-(2-methoxyphenyl)propionate. 1 H NMR (300MHz, CDCl3) δ7.27-7.15(m,2H,Ar-H),6.95-6.84(m,2H,Ar-H),3.84(s,3H,Ar-OCH3),3.69(s,3H,OCH3),2.99(t,J=7.5Hz,2H,Ar- CH 2CH2),2.65(t,J=7.5Hz,2H,Ar-CH2 CH 2).

[0042] Example 2

[0043]

[0044] Methyl 3-(2-hydroxyphenyl)propionate, i.e., compound 21 (0.01 mol, 1.8 g), was added to a three-necked flask, along with 60 mL of acetone dried over a molecular sieve, dimethyl sulfate (0.02 mol, 2.52 g), and potassium carbonate (0.025 mol, 3.45 g). The mixture was heated to reflux, and the reaction was stopped after complete TLC monitoring. The mixture was filtered, the solvent was removed under reduced pressure, and 100 mL of ethyl acetate was added. The organic phase was washed with water, saturated sodium bicarbonate solution, and saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 15:1) to give 1.84 g of compound 31, i.e., methyl 3-(2-methoxyphenyl)propionate, in 95.1% yield. The structure was confirmed by NMR.

[0045] Example 3

[0046]

[0047] Methyl 3-(2-hydroxyphenyl)propionate, i.e., compound 21 (0.01 mol, 1.8 g), was added to a three-necked flask, along with 60 mL of diethyl ether dried over a molecular sieve, 0.02 mol of methyl iodoforme (2.82 g), and 0.025 mol of potassium carbonate (3.45 g). The mixture was stirred at room temperature, and the reaction was stopped after complete TLC monitoring. The mixture was filtered, the solvent was removed under reduced pressure, and 100 mL of ethyl acetate was added. The organic phase was washed with water, saturated sodium bicarbonate solution, and saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 15:1) to give 1.69 g of compound 31, i.e., methyl 3-(2-methoxyphenyl)propionate, in 87.3% yield. The structure was confirmed by NMR.

[0048] Example 4

[0049]

[0050] Methyl 3-(2-hydroxyphenyl)propionate, i.e., compound 21 (0.01 mol, 1.8 g), was added to a three-necked flask, along with 60 mL of acetone dried over a molecular sieve, 0.02 mol of methyl iodoforme (2.82 g), and 0.025 mol of cesium carbonate (8.15 g). The mixture was stirred at room temperature, and the reaction was stopped after complete TLC monitoring. The mixture was filtered, the solvent was removed under reduced pressure, and 100 mL of ethyl acetate was added. The organic phase was washed with water, saturated sodium bicarbonate solution, and saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 15:1) to give 1.82 g of compound 31, i.e., methyl 3-(2-methoxyphenyl)propionate, in 93.7% yield. The structure was confirmed by NMR.

[0051] Example 5

[0052]

[0053] Dihydrocoumarin, i.e., compound 11 (6.7 mmol, 1.0 g), was added to a three-necked flask, followed by 30 mL of ethanol dried over a molecular sieve. Concentrated sulfuric acid (1.34 mmol, 0.13 g, 0.07 mL) was added dropwise with stirring. After the addition was complete, the mixture was heated to reflux. The reaction was stopped after TLC monitoring showed completeness. The ethanol was removed by vacuum distillation, and 50 mL of ethyl acetate was added. The organic phase was washed with water, saturated sodium bicarbonate solution, and saturated sodium chloride solution, respectively. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and dried to give 1.26 g of compound 22, i.e., ethyl 3-(2-hydroxyphenyl)propionate, in 96.0% yield. The structure was confirmed by NMR.

[0054] Example 6

[0055]

[0056] 6-Bromo-3,4-dihydrocoumarin, i.e., compound 12 (4.4 mmol, 1 g), was added to a three-necked flask, followed by 30 mL of methanol dried over a molecular sieve. Concentrated sulfuric acid (0.88 mmol, 0.09 g, 0.05 mL) was added dropwise with stirring. After the addition was complete, the mixture was heated to reflux. The reaction was stopped after TLC monitoring showed completeness. Methanol was removed by vacuum distillation, and 50 mL of ethyl acetate was added. The organic phase was washed with water, saturated sodium bicarbonate solution, and saturated sodium chloride solution, respectively. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and dried to give 1.07 g of compound 23, i.e., methyl 3-(2-hydroxy-6-bromophenyl)propionate, in 93.8% yield. The structure was confirmed by NMR.

[0057]

[0058] Methyl 3-(2-hydroxy-6-bromophenyl)propionate, i.e., compound 23 (0.01 mol, 2.59 g), was added to a three-necked flask, along with 100 mL of diethyl ether dried over a molecular sieve, 0.02 mol of methyl iodoforme (2.82 g), and 0.025 mol of potassium carbonate (3.45 g). The mixture was stirred at room temperature, and the reaction was stopped after complete TLC monitoring. The mixture was filtered, the solvent was removed under reduced pressure, and 100 mL of ethyl acetate was added. The organic phase was washed with water, saturated sodium bicarbonate solution, and saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 13:1) to give 2.42 g of compound 32, i.e., methyl 3-(2-methoxy-6-bromophenyl)propionate, in 88.6% yield. The structure was confirmed by NMR.

[0059] Example 7

[0060]

[0061] Methyl 3-(2-hydroxy-6-bromophenyl)propionate, i.e., compound 23 (0.01 mol, 2.59 g), was added to a three-necked flask. 100 mL of acetone (dried to a molecular sieve), 0.02 mol of methyl iodoforme (2.82 g), and 0.025 mol of cesium carbonate (8.15 g) were added. The mixture was stirred at room temperature, and the reaction was stopped after complete TLC monitoring. The mixture was filtered, the solvent was removed under reduced pressure, and 100 mL of ethyl acetate was added. The organic phase was washed with water, saturated sodium bicarbonate solution, and saturated sodium chloride solution, respectively. The phase was dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 13:1) to give 2.47 g of compound 32, i.e., methyl 3-(2-methoxy-6-bromophenyl)propionate, in 90.5% yield. The structure was confirmed by NMR.

[0062] Example 8

[0063]

[0064] 6-Bromo-3,4-dihydrocoumarin, i.e., compound 12 (4.4 mmol, 1 g), was added to a three-necked flask, followed by 30 mL of ethanol dried over a molecular sieve. Concentrated sulfuric acid (0.88 mmol, 0.09 g, 0.05 mL) was added dropwise with stirring. After the addition was complete, the mixture was heated to reflux. The reaction was stopped after TLC monitoring showed completeness. The ethanol was removed by vacuum distillation, and 100 mL of ethyl acetate was added. The organic phase was washed with water, saturated sodium bicarbonate solution, and saturated sodium chloride solution, respectively. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and dried to give 1.08 g of compound 24, i.e., ethyl 3-(2-hydroxy-6-bromophenyl)propionate, in 94.7% yield. The structure was confirmed by NMR.

[0065] Example 9

[0066]

[0067] Dihydrocoumarin, i.e., compound 11 (6.7 mmol, 1.0 g), was added to a three-necked flask, followed by 30 mL of isopropanol dried with molecular sieves. Concentrated sulfuric acid (1.34 mmol, 0.13 g, 0.07 mL) was added dropwise with stirring. After the addition was complete, the mixture was heated to reflux. The reaction was stopped after TLC monitoring showed complete reaction. Isopropanol was removed by vacuum distillation, and 50 mL of ethyl acetate was added. The organic phase was washed with water, saturated sodium bicarbonate solution, and saturated sodium chloride solution, respectively. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and dried to obtain 1.28 g of compound 25, i.e., isopropyl 3-(2-hydroxyphenyl)propionate, with a yield of 91.3%. The structure was confirmed to be correct by NMR.

[0068] Example 10

[0069]

[0070] Dihydrocoumarin, i.e., compound 11 (6.7 mmol, 1.0 g), was added to a three-necked flask, followed by 30 mL of n-propanol dried with molecular sieves. Concentrated sulfuric acid (1.34 mmol, 0.13 g, 0.07 mL) was added dropwise with stirring. After the addition was complete, the mixture was heated to reflux. The reaction was stopped after TLC monitoring showed complete reaction. The n-propanol was removed by vacuum distillation, and 50 mL of ethyl acetate was added. The organic phase was washed with water, saturated sodium bicarbonate solution, and saturated sodium chloride solution, respectively. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and dried to give 1.3 g of compound 26, i.e., propyl 3-(2-hydroxyphenyl)propionate, with a yield of 92.8%. The structure was confirmed to be correct by NMR.

[0071] Example 11

[0072]

[0073] Dihydrocoumarin, i.e., compound 11 (6.7 mmol, 1.0 g), was added to a three-necked flask, followed by 30 mL of n-butanol dried over a molecular sieve. Concentrated sulfuric acid (1.34 mmol, 0.13 g, 0.07 mL) was added dropwise with stirring. After the addition was complete, the mixture was heated to reflux. The reaction was stopped after TLC monitoring showed complete reaction. The n-butanol was removed by vacuum distillation, and 50 mL of ethyl acetate was added. The organic phase was washed with water, saturated sodium bicarbonate solution, and saturated sodium chloride solution, respectively. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and dried to obtain 1.33 g of compound 27, i.e., butyl 3-(2-hydroxyphenyl)propionate, with a yield of 89.2%. The structure was confirmed to be correct by NMR.

[0074] Example 12

[0075]

[0076] Dihydrocoumarin, i.e., compound 11 (6.7 mmol, 1.0 g), was added to a three-necked flask, followed by 30 mL of tert-butanol dried over a molecular sieve. Concentrated sulfuric acid (1.34 mmol, 0.13 g, 0.07 mL) was added dropwise with stirring. After the addition was complete, the mixture was heated to reflux. The reaction was stopped after TLC monitoring showed complete reaction. Isopropanol was removed by vacuum distillation. 50 mL of ethyl acetate was added. The organic phase was washed with water, saturated sodium bicarbonate solution, and saturated sodium chloride solution, respectively. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and dried to give 2.1 g of compound 28, i.e., tert-butyl 3-(2-hydroxyphenyl)propionate, in 82.4% yield. The structure was confirmed by NMR.

[0077] Example 13

[0078]

[0079] Methyl 3-(2-hydroxyphenyl)propionate, i.e., compound 21 (0.01 mol, 1.8 g), was added to a three-necked flask, along with 60 mL of isopropyl ether dried over a molecular sieve, 0.02 mol of methyl iodoforme (2.82 g), and 0.025 mol of cesium carbonate (8.15 g). The mixture was stirred at room temperature, and the reaction was stopped after complete TLC monitoring. The mixture was filtered, the solvent was removed under reduced pressure, and 100 mL of ethyl acetate was added. The organic phase was washed with water, saturated sodium bicarbonate solution, and saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 15:1) to give 1.76 g of compound 31, i.e., methyl 3-(2-methoxyphenyl)propionate, in 90.9% yield. The structure was confirmed by NMR.

[0080] Example 14

[0081]

[0082] Methyl 3-(2-hydroxyphenyl)propionate, i.e., compound 21 (0.01 mol, 1.8 g), was added to a three-necked flask, along with 60 mL of toluene dried over a molecular sieve, 0.02 mol of methyl iodoforme (2.82 g), and 0.025 mol of cesium carbonate (8.15 g). The mixture was stirred at room temperature, and the reaction was stopped after complete TLC monitoring. The mixture was filtered, the solvent was removed under reduced pressure, and 100 mL of ethyl acetate was added. The organic phase was washed with water, saturated sodium bicarbonate solution, and saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 15:1) to give 1.53 g of compound 31, i.e., methyl 3-(2-methoxyphenyl)propionate, in 78.9% yield. The structure was confirmed by NMR.

[0083] Example 15

[0084]

[0085] Methyl 3-(2-hydroxyphenyl)propionate, i.e., compound 21 (0.01 mol, 1.8 g), was added to a three-necked flask, along with 60 mL of DMF dried over a molecular sieve, 0.02 mol of methyl iodoforme (2.82 g), and 0.025 mol of cesium carbonate (8.15 g). The mixture was stirred at room temperature, and the reaction was stopped after complete TLC monitoring. The mixture was filtered, the solvent was removed under reduced pressure, and 100 mL of ethyl acetate was added. The organic phase was washed with water, saturated sodium bicarbonate solution, and saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 15:1) to give 1.80 g of compound 31, i.e., methyl 3-(2-methoxyphenyl)propionate, in 92.8% yield. The structure was confirmed by NMR.

[0086] Example 16

[0087]

[0088] Methyl 3-(2-hydroxyphenyl)propionate, i.e., compound 21 (0.01 mol, 1.8 g), was added to a three-necked flask, along with 60 mL of chloroform dried over a molecular sieve, 0.02 mol of methyl iodoform (2.82 g), and 0.025 mol of cesium carbonate (8.15 g). The mixture was stirred at room temperature, and the reaction was stopped after complete TLC monitoring. The mixture was filtered, the solvent was removed under reduced pressure, and 100 mL of ethyl acetate was added. The organic phase was washed with water, saturated sodium bicarbonate solution, and saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 15:1) to give 1.59 g of compound 31, i.e., methyl 3-(2-methoxyphenyl)propionate, in 82.3% yield. The structure was confirmed by NMR.

[0089] Example 17

[0090]

[0091] Methyl 3-(2-hydroxyphenyl)propionate, i.e., compound 21 (0.01 mol, 1.8 g), was added to a three-necked flask, along with 60 mL of dichloromethane (dried using molecular sieves), iodomethane (0.02 mol, 2.82 g), and cesium carbonate (0.025 mol, 8.15 g). The mixture was stirred at room temperature, and the reaction was stopped after complete TLC monitoring. The mixture was filtered, the solvent was removed under reduced pressure, and 100 mL of ethyl acetate was added. The organic phase was washed with water, saturated sodium bicarbonate solution, and saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 15:1) to give 1.47 g of compound 31, i.e., methyl 3-(2-methoxyphenyl)propionate, in 75.7% yield. The structure was confirmed by NMR.

[0092] Example 18

[0093]

[0094] Methyl 3-(2-hydroxyphenyl)propionate, i.e., compound 21 (0.01 mol, 1.8 g), was added to a three-necked flask, along with 60 mL of tetrahydrofuran (dried to a molecular sieve), 0.02 mol of methyl iodoforme (2.82 g), and 0.025 mol of cesium carbonate (8.15 g). The mixture was stirred at room temperature, and the reaction was stopped after complete TLC monitoring. The mixture was filtered, the solvent was removed under reduced pressure, and 100 mL of ethyl acetate was added. The organic phase was washed with water, saturated sodium bicarbonate solution, and saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 15:1) to give 1.72 g of compound 31, i.e., methyl 3-(2-methoxyphenyl)propionate, in 88.6% yield. The structure was confirmed by NMR.

[0095] Example 19

[0096]

[0097] Methyl 3-(2-hydroxyphenyl)propionate, i.e., compound 21 (0.01 mol, 1.8 g), was added to a three-necked flask, along with 60 mL of carbon tetrachloride dried over a molecular sieve, 0.02 mol of methyl iodoforme (2.82 g), and 0.025 mol of cesium carbonate (8.15 g). The mixture was stirred at room temperature, and the reaction was stopped after complete TLC monitoring. The mixture was filtered, the solvent was removed under reduced pressure, and 100 mL of ethyl acetate was added. The organic phase was washed with water, saturated sodium bicarbonate solution, and saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 15:1) to give 1.63 g of compound 31, i.e., methyl 3-(2-methoxyphenyl)propionate, in 84.3% yield. The structure was confirmed by NMR.

[0098] Example 20

[0099]

[0100] Dihydrocoumarin, i.e., compound 11 (6.7 mmol, 1.0 g), was added to a three-necked flask, followed by 30 mL of ethanol dried over a molecular sieve. Concentrated hydrochloric acid (1.34 mmol, 0.49 g, 0.11 mL) was added dropwise with stirring. After the addition was complete, the mixture was heated to reflux. The reaction was stopped after TLC monitoring showed completeness. The ethanol was removed by vacuum distillation, and 50 mL of ethyl acetate was added. The organic phase was washed with water, saturated sodium bicarbonate solution, and saturated sodium chloride solution, respectively. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and dried to give 1.22 g of compound 22, i.e., ethyl 3-(2-hydroxyphenyl)propionate, in 93.4% yield. The structure was confirmed by NMR.

[0101] Example 21

[0102]

[0103] Dihydrocoumarin (compound 11) (6.7 mmol, 1.0 g) and p-toluenesulfonic acid (1.34 mmol, 0.23 g) were added to a three-necked flask, followed by 30 mL of ethanol dried over a molecular sieve. The mixture was heated to reflux, and the reaction was stopped after complete monitoring by TLC. The ethanol was removed by vacuum distillation, and 50 mL of ethyl acetate was added. The organic phase was washed with water, saturated sodium bicarbonate solution, and saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, filtered, concentrated, and dried to give 1.11 g of compound 22, ethyl 3-(2-hydroxyphenyl)propionate, in 91.1% yield. The structure was confirmed by NMR.

[0104] Example 22

[0105]

[0106] Dihydrocoumarin, i.e., compound 11 (6.7 mmol, 1.0 g), was added to a three-necked flask, followed by 30 mL of ethanol dried over a molecular sieve. Trifluoroacetic acid (1.34 mmol, 0.152 g, 0.099 mL) was added dropwise with stirring. After the addition was complete, the mixture was heated to reflux. The reaction was stopped after TLC monitoring showed completeness. The ethanol was removed by vacuum distillation, and 50 mL of ethyl acetate was added. The organic phase was washed with water, saturated sodium bicarbonate solution, and saturated sodium chloride solution, respectively. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and dried to give 1.21 g of compound 22, i.e., ethyl 3-(2-hydroxyphenyl)propionate, in 92.0% yield. The structure was confirmed by NMR.

[0107] Example 23

[0108]

[0109] Dihydrocoumarin, or compound 11 (0.067 mol, 10 g), was added to a three-necked flask, followed by 100 mL of methanol dried over a molecular sieve. Concentrated sulfuric acid (3.34 mmol, 0.33 g, 0.18 mL) was added dropwise with stirring. After the addition was complete, the mixture was heated to reflux. The reaction was stopped after TLC monitoring showed complete reaction. Methanol was removed by vacuum distillation, and 200 mL of ethyl acetate was added. The organic phase was washed with water, saturated sodium bicarbonate solution, and saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, filtered, concentrated, and dried to obtain 11.4 g of compound 21, methyl 3-(2-hydroxyphenyl)propionate, in 94.2% yield. The structure was confirmed by NMR.

[0110] Example 24

[0111]

[0112] Dihydrocoumarin, or compound 11 (0.067 mol, 10 g), was added to a three-necked flask, followed by 100 mL of methanol dried over a molecular sieve. Concentrated sulfuric acid (6.7 mmol, 0.66 g, 0.36 mL) was added dropwise with stirring. After the addition was complete, the mixture was heated to reflux. The reaction was stopped after TLC monitoring showed complete reaction. Methanol was removed by vacuum distillation, and 200 mL of ethyl acetate was added. The organic phase was washed with water, saturated sodium bicarbonate solution, and saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, filtered, concentrated, and dried to give 11.6 g of compound 21, methyl 3-(2-hydroxyphenyl)propionate, in 95.8% yield. The structure was confirmed by NMR.

[0113] Example 25

[0114]

[0115] Dihydrocoumarin, or compound 11 (0.067 mol, 10 g), was added to a three-necked flask, followed by 100 mL of methanol dried over a molecular sieve. Concentrated sulfuric acid (0.02 mol, 1.98 g, 1.1 mL) was added dropwise with stirring. After the addition was complete, the mixture was heated to reflux. The reaction was stopped after TLC monitoring showed complete reaction. Methanol was removed by vacuum distillation, and 200 mL of ethyl acetate was added. The organic phase was washed with water, saturated sodium bicarbonate solution, and saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, filtered, concentrated, and dried to obtain 11.5 g of compound 21, methyl 3-(2-hydroxyphenyl)propionate, in 94.7% yield. The structure was confirmed by NMR.

[0116] Example 26

[0117]

[0118] Dihydrocoumarin, or compound 11 (0.067 mol, 10 g), was added to a three-necked flask, followed by 100 mL of methanol dried over a molecular sieve. Concentrated sulfuric acid (0.027 mol, 2.64 g, 1.47 mL) was added dropwise with stirring. After the addition was complete, the mixture was heated to reflux. The reaction was stopped after TLC monitoring showed complete reaction. Methanol was removed by vacuum distillation, and 200 mL of ethyl acetate was added. The organic phase was washed with water, saturated sodium bicarbonate solution, and saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, filtered, concentrated, and dried to obtain 11.4 g of compound 21, methyl 3-(2-hydroxyphenyl)propionate, in 93.8% yield. The structure was confirmed by NMR.

[0119] Example 27

[0120]

[0121] Methyl 3-(2-hydroxyphenyl)propionate, i.e., compound 21 (0.01 mol, 1.8 g), was added to a three-necked flask, along with 60 mL of acetone dried over a molecular sieve, dimethyl carbonate (0.02 mol, 1.8 g), and cesium carbonate (0.025 mol, 8.13 g). The mixture was stirred at room temperature, and the reaction was stopped after complete TLC monitoring. The mixture was filtered, the solvent was removed under reduced pressure, and 100 mL of ethyl acetate was added. The organic phase was washed with water, saturated sodium bicarbonate solution, and saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 15:1) to give 1.66 g of compound 31, i.e., methyl 3-(2-methoxyphenyl)propionate, in 85.4% yield. The structure was confirmed by NMR.

[0122] Example 28

[0123]

[0124] Methyl 3-(2-hydroxyphenyl)propionate, i.e., compound 21 (0.01 mol, 1.8 g), was added to a three-necked flask, along with 60 mL of acetone dried over a molecular sieve, methyl p-toluenesulfonate (0.02 mol, 3.72 g), and cesium carbonate (0.025 mol, 8.13 g). The mixture was stirred at room temperature, and the reaction was stopped after complete TLC monitoring. The mixture was filtered, the solvent was removed under reduced pressure, and 100 mL of ethyl acetate was added. The organic phase was washed with water, saturated sodium bicarbonate solution, and saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 15:1) to give 1.41 g of compound 31, i.e., methyl 3-(2-methoxyphenyl)propionate, in 72.6% yield. The structure was confirmed by NMR.

[0125] Example 29

[0126]

[0127] Dihydrocoumarin, i.e., compound 11 (0.67 mol, 100.0 g), was added to a three-necked flask, followed by 1 L of methanol dried over a molecular sieve. Concentrated sulfuric acid (0.134 mol, 13.1 g, 7.0 mL) was added dropwise with stirring. After the addition was complete, the mixture was heated to reflux. The reaction was stopped after TLC monitoring showed complete reaction. Methanol was removed by vacuum distillation, and 500 mL of ethyl acetate was added. The organic phase was washed with water, saturated sodium bicarbonate solution, and saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, filtered, concentrated, and dried to obtain 119.2 g of compound 21, i.e., methyl 3-(2-hydroxyphenyl)propionate, in 98.0% yield. The structure was confirmed by NMR.

[0128]

[0129] 1.0 mol (180 g) of methyl 3-(2-hydroxyphenyl)propionate, i.e., compound 21, was added to a three-necked flask. 1 L of acetone (dried to a molecular sieve), 2.0 mol (282 g) of iodomethane, and 2.5 mol (815 g) of cesium carbonate were added. The mixture was stirred at room temperature, and the reaction was stopped after complete TLC monitoring. The mixture was filtered, the solvent was removed under reduced pressure, and 1 L of ethyl acetate was added. The organic phase was washed with water, saturated sodium bicarbonate solution, and saturated sodium chloride solution, respectively. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to silica gel column chromatography (petroleum ether:ethyl acetate = 15:1) to give 180.8 g of compound 31, i.e., methyl 3-(2-methoxyphenyl)propionate, in 93.2% yield. The structure was confirmed by NMR.

[0130] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some modifications or alterations to the above-described technical content to create equivalent embodiments without departing from the scope of the present invention. Any simple modifications, equivalent changes, and alterations made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the scope of the present invention.

Claims

1. A method for preparing a phenylpropionic acid ester derivative, characterized by, The method comprises the following steps: R1 is selected from hydrogen, halogen; R2 is selected from C1-C30 alkyl; R3 is selected from C1-C30 alkyl; Compound 1 is dissolved in a first organic solvent, a catalyst is added dropwise under stirring, the molar ratio of the catalyst to compound 1 is 0.05-1:1, the reaction is completed by heating reflux, and compound 2 is obtained through post-treatment; The first organic solvent is selected from monohydric alcohol; The catalyst is selected from a protonic acid; The protonic acid is selected from sulfuric acid, hydrochloric acid, p-toluenesulfonic acid and trifluoroacetic acid; Compound 2 is dissolved in a second organic solvent, an alkylating agent and a base are added, the molar ratio of the alkylating agent to compound 2 is 1-5:1, the molar ratio of the base to compound 2 is 1-5:1, the reaction is completed at room temperature or by heating reflux, and compound 3 is obtained through post-treatment; The alkylating agent is selected from halogenated alkane and ester compound; the halogenated alkane is selected from methyl iodide, ethyl iodide and methyl bromide; and the ester compound is selected from dimethyl sulfate, methyl p-toluenesulfonate and dimethyl carbonate; The base is selected from inorganic metal base.

2. The method for preparing the phenylpropionate derivative according to claim 1, characterized in that, The molar ratio of the catalyst to compound 1 is selected from 0.05:1, 0.1:1, 0.2:1, 0.3:1 and 0.4:

1.

3. The method for preparing the phenylpropionate derivative according to claim 1, characterized in that, The monohydric alcohol is selected from methanol, ethanol, isopropanol, n-propanol, n-butanol and tert-butanol.

4. The method for preparing the phenylpropionate derivative according to claim 1, characterized in that, The second organic solvent is selected from acetone, diethyl ether, DMF, toluene, isopropyl ether, dimethylbenzene, chloroform, carbon tetrachloride, dichloromethane, tetrahydrofuran and dioxane.

5. The method for preparing the phenylpropionate derivative according to claim 1, characterized in that, The inorganic metal base is selected from potassium carbonate, cesium carbonate, sodium carbonate and lithium carbonate.

6. The method for preparing the phenylpropionate derivative according to claim 1, characterized in that, The molar ratio of the alkylating agent to compound 2 is 2:

1.

7. The method for preparing the phenylpropionate derivative according to claim 1, characterized in that, The molar ratio of the base to compound 2 is 2.5:

1.

8. The method for preparing the phenylpropionate derivative according to claim 1, characterized in that, The compound 1 is selected from one of the following structures:

9. The method for preparing the phenylpropionate derivative according to claim 1, characterized in that, The compound 2 is selected from one of the following structures:

10. The method for preparing the phenylpropionate derivative according to claim 1, characterized in that, The compound 3 is selected from one of the following structures:

Images