Preparation method of small molecule id protein inhibitor AGX51

Abstract

The application belongs to the technical field of pharmaceutical synthesis chemistry, and particularly relates to a preparation method of a small molecule Id protein inhibitor AGX51. The preparation method takes a piperonal compound 5 as a starting raw material, and obtains an olefin product compound 4 through a Wittig reaction. The compound 4 is subjected to double bond epoxidation and ring-opening reaction under alkaline conditions to synthesize a compound 3. The compound 3 is subjected to a Pinacol rearrangement reaction to obtain a compound 2. The compound 2 is subjected to Wittig olefination and hydrolysis reaction in series to obtain the compound 1. The compound 1 is subjected to reduction amination and acylation reaction in sequence to complete the synthesis of AGX51 in one pot. The structure of the target product is confirmed by MS, 1 H NMR and 13 C NMR. The structures of intermediates are confirmed by 1 H NMR. Through the preparation method, the total yield of the small molecule Id protein inhibitor AGX51 is significantly improved.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of pharmaceutical synthesis chemistry, and particularly relates to a new preparation method of a small-molecule Id protein inhibitor AGX51. BACKGROUND

[0002] AGX51 is a pan-Id (DNA binding / differentiation protein inhibitor) antagonist and degrader, and its chemical name is N-[3-(1,3-benzodioxol-5-yl)-3-(2-methoxyphenyl)propyl-N-benzyl propanamide.

[0003] Currently, there are only two synthesis routes of the compound AGX51 reported.

[0004] Synthesis route one:

[0005] In 2019, Wernerowitz et al. first disclosed the synthesis route of AGX51. The synthesis strategy is as follows: taking 3,4-(methylenedioxy)cinnamic acid 1a as the starting material, first, a Michael addition-esterification reaction catalyzed by a protonic acid is carried out with phenol 1b to generate lactone compound 1c, then an amine-ester exchange reaction is carried out with benzylamine to obtain amide compound 1d, compound 1d is synthesized under the condition of methyl iodide to obtain compound 1e, compound 1e is reduced to amine 1f by borane reduction, and compound 1f is treated with propionyl chloride to obtain compound AGX51. The synthesis route has 5 steps, and the total yield is 31.8%. The synthesis route one needs to use strong acid as the reaction solvent, which requires high quality equipment for scale-up production, and needs to use highly toxic methylating reagents, which brings certain hidden dangers to experimental safety.

[0006]

[0007] Synthesis route two:

[0008] In 2021, Benitez-Lara et al. developed another synthesis method of compound AGX51. The synthesis strategy is as follows: 2-methoxycinnamaldehyde 2a is first subjected to a conjugate addition reaction with phenylboronic acid 2b or borate 2c under the catalysis of divalent palladium to generate compound 2d, compound 2d is subjected to an indirect reductive amination reaction to obtain compound 1e, and finally compound 1e is treated with propionyl chloride to obtain compound AGX51. The synthesis route has 4 steps, and the total yield is 72.9%. However, the synthesis route two has problems such as too long reaction time (2-3 days) in the first step, high price of the catalyst, and purification difficulty caused by heavy metal residues in the product, which makes the route not easy to scale up production.

[0009]

[0010] Given the current literature reports that the AGX51 synthetic route suffers from harsh reaction conditions, safety hazards, high post-processing costs, and low derivatization rates, there is an urgent need for a new synthetic route that is low-cost, highly efficient, and better suited for industrial production. Summary of the Invention

[0011] The purpose of this invention is to provide a new preparation method for AGX51, which has the advantages of mild reaction conditions, simple and safe operation, low cost and high synthesis efficiency, and is suitable for large-scale industrial production of AGX51.

[0012] Specifically, the present invention is achieved through the following technical solutions:

[0013] In a first aspect, the present invention provides a method for preparing N-[3-(1,3-benzodioxolane-5-yl)-3-(2-methoxyphenyl)propyl-N-benzylpropionamide, the method comprising:

[0014] (1) Using compound 5 piperine as the starting material, compound 6 was reacted with compound 6 via a Wittig reaction, followed by double bond epoxidation and ring-opening reaction under alkaline conditions to synthesize compound 3;

[0015]

[0016] (2) Compound 3 undergoes the Pinacol rearrangement reaction to give compound 2;

[0017]

[0018] (3) Compound 2 undergoes a Wittig olefination tandem hydrolysis reaction to give compound 1;

[0019]

[0020] (4) Compound 1 undergoes reductive amination and acylation reactions to give AGX51.

[0021]

[0022] Further, step (1) includes:

[0023] Step a): Starting with compound 5 piperine, it undergoes a Wittig reaction with Wittig reagent 6 in the presence of a base to give the olefin product compound 4; and

[0024]

[0025] Step b): Compound 4 was synthesized into compound 3 via double bond epoxidation and ring-opening reaction under basic conditions.

[0026]

[0027] Further, the base used in step a) is selected from t-BuONa, n-BuLi, t-BuOK, NaHMDS, NaH or EtONa, preferably t-BuOK.

[0028] Further, the solvent used in step a) is THF.

[0029] Further, in step a), the molar feed ratio of Wittig reagent 6 to compound 5 is (1.5-3):1, preferably 2.5:1.

[0030] Further, in step a), the molar feed ratio of base to compound 5 is (1-3):1, preferably 2:1.

[0031] Further, the reaction temperature of step a) is -20°C.

[0032] Further, the reaction time of step a) is 0.5h to 1.0h, preferably 0.5h.

[0033] Further, in step b), double bond epoxidation reaction is carried out using m-CPBA. Further, the molar feed ratio of m-CPBA to compound 4 is (0.1-0.2):1.

[0034] Further, the solvent used in step b) is dichloromethane.

[0035] Further, the solvent used in step (2) is DCE or THF, preferably DCE.

[0036] Further, in step (2), a catalyst system NFSI / FeCl3-6H2O is used.

[0037] Further, in step (2), the catalyst loading and ratio, i.e. the molar ratio of NFSI to FeCl3-6H2O is (5-10):1, preferably 5:1.

[0038] Further, the reaction temperature of step (2) is 40°C to 60°C, preferably 60°C.

[0039] Further, the reaction time of step (2) is 8h to 12h, preferably 8h.

[0040] Further, in step (3), Wittig olefination tandem hydrolysis reaction is carried out using MOMPPh3Cl reagent. Further, the molar feed ratio of MOMPPh3Cl reagent to compound 2 is 1:1.

[0041] Further, the solvent used in step (3) is THF.

[0042] Furthermore, in step (4), benzylamine, NaBH3CN, and AcOH are used to carry out the reductive amination reaction. Furthermore, the molar ratio of benzylamine, NaBH3CN, and AcOH to compound 1 is 1.5:1.5:1:1.

[0043] Furthermore, in step (4), Et3N and propionyl chloride are used for the acylation reaction. Furthermore, the molar ratio of Et3N and propionyl chloride to compound 1 is 1:1:1.

[0044] Furthermore, the solvent used in step (4) is MeOH.

[0045] Furthermore, the preparation method of the present invention can be represented as follows:

[0046]

[0047] Compared with the prior art, the present invention has the following beneficial effects:

[0048] The novel synthetic route for AGX51 provided by this invention reduces one step compared to the previously disclosed synthetic route one, and significantly improves the overall yield to 41.6%. Regarding reaction conditions, the previously disclosed synthetic route one requires a strong acid as a reaction solvent, placing high demands on equipment quality for scale-up production, and also requires highly toxic methylating agents, posing certain safety risks. Furthermore, the previously disclosed synthetic route two has an excessively long reaction time and requires a relatively expensive catalyst. The synthetic route of this invention overcomes these drawbacks, employing an inexpensive and readily available catalyst, simplifying post-processing, and providing relatively mild reaction conditions, making it more suitable for industrial production. Notably, the synthetic route of this invention offers greater advantages in derivatization. Attached Figure Description

[0049] The accompanying drawings are provided to further illustrate the invention and form part of the specification. They are used in conjunction with embodiments of the invention to explain the invention and do not constitute a limitation thereof. In the drawings:

[0050] Figure 1 Compound 4 synthesized in Example 1 1 H NMR spectrum;

[0051] Figure 2 Compound 3 synthesized in Example 1 1 H NMR spectrum;

[0052] Figure 3 Compound 2 synthesized in Example 1 1 H NMR spectrum;

[0053] Figure 4HNMR spectrum of the compound 1 synthesized in Example 1 1 HNMR spectrum of the compound AGX51 synthesized in Example 1

[0054] Figure 5 HNMR spectrum of the compound AGX51 synthesized in Example 1 1 HNMR spectrum of the compound AGX51 synthesized in Example 1

[0055] Figure 6 HNMR spectrum of the compound AGX51 synthesized in Example 1 13 HNMR spectrum of the compound AGX51 synthesized in Example 1 DETAILED DESCRIPTION

[0056] In the present application, the abbreviations of substituents used have the general meaning in the art, unless otherwise specified. A list of abbreviations is shown below.

[0057] List of abbreviations used in Table 1

[0058]

[0059] The present application is described in detail below with reference to the following examples. The examples are presented to better illustrate the present application and should not be construed as limiting the present application.

[0060] Unless otherwise specified, the techniques and conditions in the examples are performed according to the techniques and conditions described in the literature or according to the product manual. Unless otherwise specified, the reagents and instruments used are conventional products that can be purchased through a regular channel.

[0061] Unless otherwise specified, the experimental methods in the following examples are conventional methods. Unless otherwise specified, the test materials used in the following examples are commercially available products.

[0062] Unless otherwise specified, the percentages and parts in the present application are weight percentages and weight parts.

[0063] Example 1

[0064] Synthesis of compound 4

[0065] (Z / E)-5-(2-methoxystyryl)benzo-1,3-dioxol

[0066]

[0067] To a dry round bottom flask was added compound 6 (16.2 g, 2.6 mmol) and anhydrous THF (100 mL), the reaction was cooled to 20 °C, t-BuOK (18.0 g, 5.6 mmol) was added slowly under nitrogen protection, stirred at this temperature for 0.5 h, compound 5 (16.2 g, 1.3 mmol) was dissolved in anhydrous THF and added slowly dropwise into the reaction system, then moved to room temperature and continued to stir for 5 h, TLC monitoring showed that the starting material was consumed. Extracted with ethyl acetate (20 mL x 3), combined the organic phase, washed with saturated brine (5 mL x 1), dried over anhydrous sodium sulfate, removed the solvent by rotary evaporator, purified by flash column chromatography with petroleum ether / ethyl acetate (3:1) as the mobile phase to obtain compound 4 (Z / E isomers) as a white solid with a yield of 85.9%. Z-type isomer: 1 HNMR (600 MHz, CDC13) δ 7.16-7.08 (m, 2H), 6.79 (d, J = 8.2 Hz, 1H), 6.70 (t, J = 7.6 Hz, 1H), 6.67-6.60 (m, 2H), 6.57 (d, J = 7.9 Hz, 1H), 6.49 (d, J = 12.2 Hz, 1H), 6.43 (d, J = 12.1 Hz, 1H), 5.78 (s, 2H), 3.73 (s, 3H) (see Figure 1 ).

[0068] Synthesis of compound 3

[0069] 1-(BENZO-1, 3-DIOXOL-5-YL)-2-(2-METHOXYPHENYL)ETHANE-1, 2-DIOL

[0070]

[0071] To a dry round bottom flask was added compound 4 (20.0 g, 52.6 mmol) and anhydrous dichloromethane, the reaction was cooled to 0 °C, m-CPBA (18.0 g, 5.6 mmol) was added slowly, moved to room temperature and stirred for 12 h, TLC monitoring showed that the starting material was consumed. The reaction was filtered with diatomite to remove insoluble matter, the filtrate was extracted with dichloromethane (20 mL x 3), the combined organic phase was washed with saturated sodium sulfite aqueous solution (10 mL x 2), saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, the solvent was removed by rotary evaporator to obtain the crude product.

[0072] The crude product was dissolved in THF and cooled to 0 °C, 10 mL of 10% NaOH aqueous solution was slowly added into the mixture, stirred at room temperature for 3 h, TLC monitoring showed no remaining starting material. 0.5 M HCl aqueous solution was added into the reaction solution dropwise to adjust the pH of the system to neutral, extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, the solvent was removed by rotary evaporator, purified by flash column chromatography with petroleum ether / ethyl acetate (3:1) as mobile phase to give compound 3 as colorless oil in 74.2% yield. 1 HNMR (600 MHz, DMSO-d6) δ 7.19 - 7.12 (m, 1H), 7.08 - 6.85 (m, 2H), 6.85 - 6.69 (m, 3H), 6.66 - 6.58 (m, 1H), 5.95 - 5.89 (m, 2H), 5.22 - 5.02 (m, 2H), 5.02 - 4.78 (m, 1H), 4.66 - 4.41 (m, 1H), 3.66 (s, 3H) (see Figure 2 ).

[0073] Synthesis of compound 2

[0074] 2-(B enzo-1,3-dioxol-5-yl)-2-(2-methoxyphenyl)acetaldehyde

[0075]

[0076] Into a dry flask was added compound 3 (3.1 g, 1.7 mmol), NFSI (0.1 g, 0.5 mmol), FeCl3-6H2O (0.1 g, 0.1 mmol) and 1,2-dichloroethane (15 mL), the reaction solution was slowly warmed to 60 °C, stirred for 8 h, TLC monitoring showed no remaining starting material. The solvent was removed by rotary evaporator, purified by flash column chromatography with petroleum ether / ethyl acetate (3:1) as mobile phase to give compound 2 as colorless oil in 87.9% yield. 1 HNMR (600 MHz, DMSO-d6) δ 9.80 (d, J = 1.0 Hz, 1H), 7.33 - 7.28 (m, 1H), 7.10 (dd, J = 7.5, 1.7 Hz, 1H), 7.06 (dd, J = 8.2, 1.1 Hz, 1H), 6.95 (td, J = 7.5, 1.1 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.79 (d, J = 1.8 Hz, 1H), 6.67 (dd, J = 8.0, 1.8 Hz, 1H), 5.98 (dd, J = 5.8, 1.0 Hz, 2H), 5.06 (s, 1H), 3.76 (s, 3H) (see Figure 3 ).

[0077] Synthesis of compound 1

[0078] 3-(benzo-1,3-dioxol-5-yl)-3-(2-methoxyphenyl)propanal

[0079]

[0080] To a dry round bottom flask was added compound MOM PPh3Cl reagent (5.2 g, 1.6 mmol) and anhydrous THF (10 mL), the reaction was cooled to 78 °C, and LiHMDS (1 M in THF, 5.6 mL) was added slowly under nitrogen protection, the reaction was stirred at room temperature for 0.5 h, then the reaction was cooled to 0 °C, compound 2 (5.2 g, 1.6 mmol) was dissolved in anhydrous THF and added slowly into the flask, finally the reaction was stirred at room temperature for 6 h, TLC monitoring showed no remaining starting material. 5 mL 2M aqueous HC1 was added to the reaction, and the reaction was stirred at room temperature until the starting material was completely reacted. The reaction was extracted with ethyl acetate (30 mL x 3), the organic phase was combined and washed with saturated aqueous sodium bicarbonate (10 mL x 1) and saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The product was purified by flash column chromatography using petroleum ether / ethyl acetate (5:1) as the mobile phase to give compound 1 as a white solid in 92.6% yield. 1 H NMR (600 MHz, DMSO-d6) δ 9.59 (t, J = 1.7 Hz, 1H), 7.22 (dd, J = 7.6, 1.7 Hz, 1H), 7.17 (td, J = 7.7, 1.7 Hz, 1H), 6.94 (dd, J = 8.2, 1.2 Hz, 1H), 6.89 (td, J = 7.5, 1.1 Hz, 1H), 6.84 (d, J = 2.0 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 6.72 (dd, J = 8.0, 1.8 Hz, 1H), 5.93 (dd, J = 5.7, 1.1 Hz, 2H), 4.86 (t, J = 7.9 Hz, 1H), 3.76 (s, 3H), 3.19 - 3.04 (m, 2H) (see Figure 4 ).

[0081] Synthesis of compound AGX51

[0082] N-[3-(1,3-benzodioxol-5-yl)-3-(2-methoxyphenyl)propyl]-N-benzylpropanamide

[0083]

[0084] Into a dry round bottom flask, compound 1 (0.5 g, 29.0 mmol), benzylamine (7.9 g, 43.5 mmol), NaBH3CN (7.9 g, 43.5 mmol), AcOH (10.0 g, 29.0 mmol) and anhydrous MeOH (10 mL) were added successively, purged with nitrogen for 3 times, stirred at room temperature, TLC monitored until no starting material was left. The reaction was cooled to 0 °C, Et3N (10.0 g, 29.0 mmol) was added, propionyl chloride (10.0 g, 29.0 mmol) was added dropwise slowly, stirred at room temperature for 1 min, TLC monitored until no starting material was left. 2 mL saturated aqueous NaHC03was added to the mixture, extracted with ethyl acetate (50 mL x 3), the combined organic phase was washed with saturated brine (10 mL x 1), dried over anhydrous Na2S04, the solvent was removed by rotary evaporator, purified by flash column chromatography with petroleum ether / ethyl acetate (5: 1) as mobile phase to give compound AGX51 as a white solid in 83.6% yield. 1 HNMR and 13 C NMR data are shown in Table 1 Figure 5 and Figure 6 .

[0085] Example 2 (investigation of the synthesis process of compound 4)

[0086] Screening of base types

[0087] The reaction is a classic Wittig reaction. According to the literature, the factors affecting the yield of the reaction mainly include: the equivalent of Wittig reagent, the type and equivalent of base, and the reaction temperature. Therefore, the above factors are the key investigation direction of the reaction. First, the effect of the type of base on the yield of the reaction was investigated.

[0088] Table 2 Screening of base types

[0089]

[0090] Note: Each group of experiments was carried out with the same batch of substrate 51.0 g. Reaction conditions: the amount of Wittig reagent and base was equal to 5 equivalents of the substrate, the hydrogenation reaction temperature was 20 °C, and the time was 0.5 h. [a] Isolated yield. [b],[c] Raw material recovery yield.

[0091] The above 6 different intensity bases are derived from the commonly used base types in such reactions. Proton exchange occurs between the base and the Wittig reagent in the reaction system to produce a highly active phosphorus ylide. The latter undergoes nucleophilic addition reaction with the aldehyde group, goes through a phosphorus oxetane intermediate, and finally produces an olefin product. For this reaction, the Z / E isomer ratio of the generated olefin mainly depends on the energy level of the phosphorus oxetane ring formed in different configurations.

[0092] The experimental results show that when NaH and EtONa are selected as the base, the yield is low due to insufficient base strength, resulting in a large amount of remaining raw material within the specified reaction time (Entries 5 and 6). In the investigation of t-BuONa, t-BuOK and NaHMDS, it is found that t-BuOK is more suitable for the basicity requirement of Wittig reagent, and the yield is higher (Entries 1, 3 and 4). From the yield point of view, it is most suitable to select n-BuLi as the base for this step reaction (Entry 2), but considering the flammable, explosive and inconvenient operation of n-BuLi, combined with the actual situation of industrial production, it is decided to use t-BuOK as the base reagent for this step reaction, and further investigate the amount and hydrogenation time.

[0093] Investigation of the feeding ratio of Wittig reagent and base and the hydrogenation time

[0094] Table 3 Investigation of the feeding ratio of Wittig reagent and base and the hydrogenation time

[0095]

[0096] Note: The reaction time of this step is divided into two stages: 1) t-BuOK and Wittig reagent 6 hydrogenation time: 2) after the substrate 5 is added, the reaction continues at the specified reaction temperature for the specified time. The second stage reaction time is determined by TLC monitoring until the raw material is consumed. [a] Hydrogenation time at -20°C. [b] Separation yield.

[0097] The experimental results show that when the feeding amount of Wittig reagent and t-BuOK is controlled at 1 eq., the yield is basically unchanged by prolonging the hydrogenation time (Entries 1 and 2); simultaneously increasing the feeding amount of Wittig reagent and t-BuOK has a significant effect on the improvement of reaction yield (Entries 1, 4 and 7); reducing the feeding ratio of Wittig reagent and t-BuOK will slightly improve the reaction yield (Entries 1, 3, 4 and 6); prolonging the reaction time has not yet shown obvious effect on the improvement of yield (Entries 1, 2, 4, 5, 7 and 8). The experiment shows that when the equivalent of Wittig reagent and t-BuOK is increased to 3 eq., the reaction yield reaches the highest and begins to stabilize (Entries 7 and 8).

[0098] In summary, the optimal conditions for Wittig reaction are as follows: THF as solvent, t-BuOK (2.5 eq.) as base, the amount of Wittig reagent is 2.0 eq., the hydrogenation reaction temperature is 20°C, and the time is 0.5 h.

[0099] Example 3 (Investigation of the synthesis process of compound 2)

[0100] Pinacol rearrangement is a highly efficient method for constructing carbon-carbon bond, which plays an important role in the synthesis of many drug molecules. The classical Pinacol rearrangement uses catalytic conditions of excess protonic acid such as H2SO4, H3PO4, etc. strong acid. Pinacol rearrangement under such conditions usually has the disadvantages of low selectivity, low yield and severe reaction conditions, in addition, the strong acidic reaction conditions are more serious corrosion to the reaction equipment, and easy to cause environmental pollution problems. Therefore, it is of great significance to optimize the reaction conditions. The inventors developed a new catalyst system (NFSI / FeCl3·6H2O), which showed good applicability to the reaction. According to the characteristics of the reaction and the previous research experience, the effects of catalyst loading and ratio, solvent effect, reaction temperature and time on the yield of the reaction were investigated.

[0101] Table 4 Pinacol rearrangement reaction condition screening

[0102]

[0103] Note: Each group of experiments is based on the same batch of substrate 30.3g. The reaction time is the duration of the reaction after reaching the target temperature. [a] Separation yield.

[0104] The experimental results show that, first, control the catalyst loading and ratio, solvent and reaction time unchanged, investigate the effect of reaction temperature on the yield. Experiments show that, with the increase of temperature, the yield is obviously improved, the reaction temperature reaches 60℃, the yield reaches the highest (Entries 1-3), then replace the solvent with THF at this temperature, investigate the effect of solvent on the yield, found that the yield is slightly reduced. Then increase the catalyst loading, whether to reduce the temperature or shorten the reaction time, the yield is maintained at a high level (Entries 8-10). When the catalyst loading and ratio is controlled at 10:1, the reaction time is prolonged, the yield is almost unchanged, and the yield is reduced when THF is used as the solvent (Entries 5-7).

[0105] In summary, the optimal conditions for Pinacol rearrangement reaction are as follows: DCE as solvent, catalyst dosage NFSI (5mol%) / FeCl3·6H2O (1mol%), reaction temperature 60℃, time 8h.

[0106] It is apparent that the above-mentioned embodiments are only examples for clearly illustrating the present application and are not intended to limit the embodiments of the present application. Those skilled in the art can make various modifications and variations without departing from the spirit and scope of the present application. Thus, if these modifications and variations of the present application fall within the scope of the claims of the present application and their equivalents, it is also intended to include these modifications and variations.

Claims

1. A kind N -[3-(1,3-benzodioxolane-5-yl)-3-(2-methoxyphenyl)propyl- N The method for preparing β-benzylpropionamide is characterized by: Includes the following steps: (1) Using compound 5 piperine as the starting material, compound 3 is synthesized. Step (1) includes: Step a): Using compound 5 (piperaldehyde) as the starting material, compound 4 is synthesized. The specific reaction route is shown below: ， The alkali is t -BuOK, and Step b): Compound 4 reacts to synthesize compound 3. The specific reaction route is shown below: ； (2) Compound 3 reacts to give compound 2. The specific reaction route is shown below: ； (3) Compound 2 reacts to give compound 1. The specific reaction route is shown below: ； as well as (4) Compound 1 reacts to give N -[3-(1,3-benzodioxolane-5-yl)-3-(2-methoxyphenyl)propyl- N -Benzylpropionamide (AGX51), the specific reaction route is shown below: 。 2. As described in claim 1 N -[3-(1,3-benzodioxolane-5-yl)-3-(2-methoxyphenyl)propyl- N The method for preparing β-benzylpropionamide is characterized by: In step a), the molar ratio of Wittig reagent 6 to compound 5 is (1.5-3):1, and the molar ratio of base to compound 5 is (1-3):

1.

3. As described in claim 2 N -[3-(1,3-benzodioxolane-5-yl)-3-(2-methoxyphenyl)propyl- N The method for preparing β-benzylpropionamide is characterized by: The reaction temperature in step a) is -20℃, and the reaction time in step a) is 0.5h to 1.0h.

4. The method according to claim 3 N -[3-(1,3-benzodioxolane-5-yl)-3-(2-methoxyphenyl)propyl- N The method for preparing β-benzylpropionamide is characterized by: In step (2), the molar ratio of catalyst NFSI to FeCl3•6H2O is (5-10):

1.

5. The method according to claim 4 N -[3-(1,3-benzodioxolane-5-yl)-3-(2-methoxyphenyl)propyl- N The method for preparing β-benzylpropionamide is characterized by: The reaction time for step (2) is 8 to 12 hours.

6. The method according to claim 5 N -[3-(1,3-benzodioxolane-5-yl)-3-(2-methoxyphenyl)propyl- N The method for preparing β-benzylpropionamide is characterized by: In step (3), the molar ratio of MOMPPh3Cl reagent to compound 2 is 1:

1.

7. The method according to claim 6 N -[3-(1,3-benzodioxolane-5-yl)-3-(2-methoxyphenyl)propyl- N The method for preparing β-benzylpropionamide is characterized by: In step (4), benzylamine, NaBH3CN and AcOH are used for the reductive amination reaction. The molar ratio of benzylamine, NaBH3CN and AcOH to compound 1 is 1.5:1.5:1:

1. Et3N and propionyl chloride are used for the acylation reaction. The molar ratio of Et3N and propionyl chloride to compound 1 is 1:1:1.

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