Method for preparing (S)-2-((3-((benzo[d][1,3]dioxopentane-5-oxo)methyl)benzyl)-amino)propionamide

Abstract

This application relates to a method for preparing (S)-2-((3-((benzo[d][1,3]dioxopenta-5-oxy)methyl)benzyl)-amino)propionamide of formula I or a pharmaceutically acceptable salt thereof, and also to an intermediate for preparing the compound. This method is low-cost, simple to operate, safe and environmentally friendly, exhibits high reaction selectivity and high yield, and is suitable for large-scale industrial production.

Description

Technical Field

[0001] This application relates to a method for preparing (S)-2-((3-((benzo[d][1,3]dioxopenta-5-oxo)methyl)benzyl)-amino)propionamide of Formula I or a pharmaceutically acceptable salt thereof, and also to an intermediate for preparing the compound. This method is low-cost, simple to operate, safe and environmentally friendly, exhibits high reaction selectivity and high yield, and is suitable for large-scale industrial production. Background Technology

[0002] ( S )-2-((3-((benzo[ d [1,3]dioxopentane-5-oxo)methyl)benzyl)-amino)propionamide is a synthetically produced compound with the structure shown in Formula I: .

[0003] This compound is a sodium ion channel inhibitor. Patent application CN104761531A discloses a method for synthesizing this compound, comprising: using isophthalaldehyde (1) as a raw material, reducing it with sodium borohydride to obtain m-hydroxymethylbenzaldehyde (2); reacting m-hydroxymethylbenzaldehyde (2) with sesamol under the action of triphenylphosphine (PPh3) and diethyl azodicarbonate (DEAD) to obtain 3-(benzo[ d [1,3]dioxolane-5-oxomethyl)benzaldehyde (4),3-(benzo[ d [1,3]dioxapentane-5-oxomethyl)benzaldehyde (4) was reacted with L-alanine hydrochloride under alkaline conditions and reduced by sodium cyanoborohydride to obtain ( S )-2-((3-((benzo[ d [1,3]dioxopentane-5-oxo)methyl)benzyl)-amino)propionamide.

[0004]

[0005] The above-mentioned methods in the prior art have the following shortcomings: a) When preparing m-hydroxymethylbenzaldehyde (2), the product needs to be purified by column chromatography, which is not suitable for large-scale preparation; b) the intermediate 3-(benzo[ d The synthesis of [1,3]dioxapentane-5-oxomethyl)benzaldehyde (4) uses triphenylphosphine (PPh3) and diethyl azodicarbonate (DEAD), which generates triphenylphosphine oxyphosphate byproducts that need to be removed by column chromatography, making it unsuitable for large-scale production; c) final product ( S )-2-((3-((benzo[ dThe synthesis of [1,3]dioxapentane-5-oxo)methyl)benzyl)-amino)propionamide uses expensive sodium cyanoborohydride, which easily produces highly toxic free cyanide ions. The reaction has low selectivity and easily generates byproducts that reduce aldehyde groups, making the post-processing steps cumbersome. Column chromatography is required, but the yield of this step is less than 30%, which is not conducive to industrial production. d) The overall yield is low, only 17.6%.

[0006]

[0007] There is an urgent need for green, economical, efficient, and large-scale preparation methods. S )-2-((3-((benzo[ d [1,3] Method for dioxopentane-5-oxo)methyl)benzyl)-amino)propionamide. Summary of the Invention

[0008] The first aspect of this application provides a method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof, comprising:

[0009] 1) React the compound shown in Formula 3 with sesamol to produce the compound shown in Formula 4; 2) React the compound L-propanediamide shown in Formula 4 to produce the compound shown in Formula I.

[0010] Where R is a chlorine, bromine, iodine, methanesulfonate group (-OMs, CH3S(O)2O-), trifluoromethanesulfonate group (-OTf, CF3S(O)2O-), or p-toluenesulfonate group (-OTs, p -CH3C6H4S(O)2O-).

[0011] In some embodiments, step 1) includes reacting the compound of formula 3 with sesamol in a first solvent and in the presence of a first base reagent to produce the compound of formula 4.

[0012] In some embodiments, the first solvent is selected from water, acetonitrile, tetrahydrofuran, ethanol, methanol, N,N-dimethylformamide, and any combination thereof. In some embodiments, the first solvent is tetrahydrofuran or N,N-dimethylformamide. In some embodiments, the first solvent is tetrahydrofuran.

[0013] In some embodiments, the first base reagent is selected from sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, and N,N-diisopropylethylamine. In some embodiments, the first base reagent is cesium carbonate.

[0014] In some embodiments, the molar ratio of the compound shown in Formula 3 to sesamol is 1:0.8 to 1.2. In some embodiments, the molar ratio of the compound shown in Formula 3 to sesamol is 1:1.

[0015] In some embodiments, the ratio of the compound of Formula 3 to the first solvent is 1000 g : 2-50 L solvent. In some embodiments, the ratio of the compound of Formula 3 to the first solvent is 1000 g : 5-20 L solvent. In some embodiments, the ratio of the compound of Formula 3 to the first solvent is 1000 g : 10-15 L solvent. In some embodiments, the ratio of the compound of Formula 3 to the first solvent is 1000 g : 12 L solvent.

[0016] In some embodiments, the molar ratio of the compound shown in Formula 3 to the first base reagent is 1:1 to 2. In some embodiments, the molar ratio of the compound shown in Formula 3 to the first base reagent is 1:1.2 to 1.8. In some embodiments, the molar ratio of the compound shown in Formula 3 to the first base reagent is 1:1.5.

[0017] In some embodiments, step 1) comprises: reacting the compound of Formula 3 with sesamol in a first solvent and in the presence of a first base reagent at a temperature of 20–120 °C (e.g., 20–80 °C, 25–66 °C) for 0.5–8 hours (e.g., 0.5–4 hours, 1 hour, 2 hours, 3 hours) to produce the compound of Formula 4.

[0018] In some embodiments, step 2) includes: reacting the compound of formula 4 with L-propanediamide in a second solvent and in the presence of a first reducing agent and a second base reagent to produce the compound of formula I.

[0019] In some embodiments, the second solvent is selected from acetonitrile, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, toluene, and any combination thereof. In some embodiments, the second solvent is acetonitrile or tetrahydrofuran.

[0020] In some embodiments, the first reducing agent is selected from sodium triacetoxyborohydride, potassium triacetoxyborohydride, and any combination thereof. In some embodiments, the first reducing agent is sodium triacetoxyborohydride.

[0021] In some embodiments, the second base reagent is selected from triethylamine, N,N-diisopropylethylamine, pyridine, sodium carbonate, sodium hydroxide, triethylenediamine, and any combination thereof. In some embodiments, the second base reagent is triethylamine or N,N-diisopropylethylamine.

[0022] In some embodiments, the molar ratio of the compound of Formula 4 to L-alanine is 1:0.5 to 2. In some embodiments, the molar ratio of the compound of Formula 4 to L-alanine is 1:0.8 to 1.8. In some embodiments, the molar ratio of the compound of Formula 4 to L-alanine is 1:1 to 1.5. In some embodiments, the molar ratio of the compound of Formula 4 to L-alanine is 1:1.3.

[0023] In some embodiments, the ratio of the compound shown in Formula 4 to the second solvent is 1000 g : 4~8 L. In some embodiments, the ratio of the compound shown in Formula 4 to the second solvent is 1000 g : 6 L.

[0024] In some embodiments, the molar ratio of the compound shown in Formula 4 to the first reducing agent is 1:1 to 5. In some embodiments, the molar ratio of the compound shown in Formula 4 to the first reducing agent is 1:2 to 4. In some embodiments, the molar ratio of the compound shown in Formula 4 to the first reducing agent is 1:2.5 to 3.5. In some embodiments, the molar ratio of the compound shown in Formula 4 to the first reducing agent is 1:3.

[0025] In some embodiments, the molar ratio of the compound shown in Formula 4 to the second base reagent is 1:0.8 to 2. In some embodiments, the molar ratio of the compound shown in Formula 4 to the second base reagent is 1:1 to 1.8. In some embodiments, the molar ratio of the compound shown in Formula 4 to the second base reagent is 1:1.2 to 1.6. In some embodiments, the molar ratio of the compound shown in Formula 4 to the second base reagent is 1:1.4.

[0026] In some embodiments, step 2) comprises: reacting the compound of Formula 4 with L-propanediamide in a second solvent and in the presence of a first reducing agent and a second base reagent at a temperature of 0–100 °C for 0.5–24 hours (e.g., 0.5–6 hours, 2–5 hours, 3 hours) to produce the compound of Formula I.

[0027] In some embodiments, step 2) comprises: reacting the compound of Formula 4 with L-propanediamide in a second solvent and in the presence of a first reducing agent and a second base reagent at a temperature of 20–50 °C for 0.5–24 hours (e.g., 0.5–6 hours, 2–5 hours, 3 hours) to produce the compound of Formula I.

[0028] In some embodiments, step 2) comprises: reacting the compound of Formula 4 with L-propanediamide in a second solvent and in the presence of a first reducing agent and a second base reagent at a temperature of 25–35 °C for 0.5–24 hours (e.g., 0.5–6 hours, 2–5 hours, 3 hours) to produce the compound of Formula I.

[0029] In some embodiments, step 1) includes: reacting the compound shown in Formula 3 with sesamol to generate the compound shown in Formula 4, and then using the reaction solution containing the compound shown in Formula 4 directly after removing insoluble solids for the reaction in step 2).

[0030] In some embodiments, the method described in the first aspect of this application further includes: preparing the compound shown in Formula 3. Preparing the compound shown in Formula 3 involves reacting m-hydroxymethylbenzaldehyde (2) with a substitution reagent in a third solvent to generate the compound shown in Formula 3.

[0031]

[0032] In some embodiments, the third solvent is selected from ethyl acetate, dichloromethane, isopropanol, chloroform, toluene, xylene, n-hexane, and any combination thereof.

[0033] In some embodiments, the third solvent is toluene or dichloromethane. In some embodiments, the substitution reagent is HR. a CH3S(O)2OR a CF3S(O)2OR a , p -CH3C6H4S(O)2OR a 、S(O)(R a 2. P(R) a 3. P(R) a )5 or , where R a The reagents are chlorine, bromine, and iodine. In some embodiments, the substitution reagent is HBr. In some embodiments, the substitution reagent is an aqueous solution of HBr or an acetic acid solution of HBr. In some embodiments, the substitution reagent is a 48% aqueous solution of HBr or a 33% acetic acid solution of HBr.

[0034] In some embodiments, the preparation of the compound shown in Formula 3 comprises: reacting m-hydroxymethylbenzaldehyde with a substitution reagent in a third solvent at a temperature of 0–140°C for 2–8 hours (e.g., 2–7 hours, 3–6 hours, 5 hours) to produce the compound shown in Formula 3.

[0035] In some embodiments, the preparation of the compound shown in Formula 3 comprises: reacting m-hydroxymethylbenzaldehyde with a substitution reagent in a third solvent at a temperature of 20–120°C for 2–8 hours (e.g., 2–7 hours, 3–6 hours, 5 hours) to produce the compound shown in Formula 3.

[0036] In some embodiments, the preparation of the compound shown in Formula 3 comprises: reacting m-hydroxymethylbenzaldehyde with a substitution reagent in a third solvent at a temperature of 60–80°C for 2–8 hours (e.g., 2–7 hours, 3–6 hours, 5 hours) to produce the compound shown in Formula 3.

[0037] In some embodiments, the ratio of hydroxymethylbenzaldehyde to the substitution reagent is 1000 g : 1.5~3 L. In some embodiments, the ratio of hydroxymethylbenzaldehyde to the substitution reagent is 1000 g : 2 L.

[0038] In some embodiments, the ratio of hydroxymethylbenzaldehyde to the third solvent is 1000 g : 2-4 L. In some embodiments, the ratio of hydroxymethylbenzaldehyde to the third solvent is 1000 g : 3 L.

[0039] In some embodiments, the method described in the first aspect of this application further includes: preparing m-hydroxymethylbenzaldehyde. The preparation of m-hydroxymethylbenzaldehyde includes: reducing m-phthalaldehyde (1) with a second reducing agent to generate m-hydroxymethylbenzaldehyde (2).

[0040]

[0041] In some embodiments, the preparation of m-hydroxymethylbenzaldehyde includes: reducing m-phthalaldehyde in a fourth solvent using a second reducing agent to generate m-hydroxymethylbenzaldehyde; In some embodiments, the preparation of m-hydroxymethylbenzaldehyde includes reducing m-phthalaldehyde in a fourth solvent at a temperature of -30 to 50°C using a second reducing agent for 2 to 10 hours (e.g., 4 to 8 hours, 5 hours, 6 hours) to generate m-hydroxymethylbenzaldehyde.

[0042] In some embodiments, the preparation of m-hydroxymethylbenzaldehyde includes reducing m-phthalaldehyde in a fourth solvent at a temperature of -10 to 10°C using a second reducing agent for 2 to 10 hours (e.g., 4 to 8 hours, 5 hours, 6 hours) to generate m-hydroxymethylbenzaldehyde.

[0043] In some embodiments, the preparation of m-hydroxymethylbenzaldehyde includes: reducing m-phthalaldehyde in a fourth solvent at a temperature of 0-5°C using a second reducing agent for 2-10 hours (e.g., 4-8 hours, 5 hours, 6 hours) to generate m-hydroxymethylbenzaldehyde.

[0044] In some embodiments, the ratio of isophthalaldehyde to the fourth solvent is 1000 g : 0.5~100 L solvent. In some embodiments, the ratio of isophthalaldehyde to the fourth solvent is 1000 g : 10~20 L solvent. In some embodiments, the ratio of isophthalaldehyde to the fourth solvent is 1000 g : 14~18 L.

[0045] In some embodiments, the molar ratio of isophthalaldehyde to the second reducing agent is 1:0.1 to 0.5. In some embodiments, the molar ratio of isophthalaldehyde to the second reducing agent is 1:0.2 to 0.4. In some embodiments, the molar ratio of isophthalaldehyde to the second reducing agent is 1:0.3.

[0046] In some embodiments, the second reducing agent is sodium borohydride, potassium borohydride, lithium aluminum hydride, or a boranetetrahydrofuran complex. In some embodiments, the second reducing agent is sodium borohydride or potassium borohydride. In some embodiments, the second reducing agent is sodium borohydride.

[0047] In some embodiments, the fourth solvent is selected from anhydrous ethanol, anhydrous methanol, tetrahydrofuran, ethyl acetate, isopropanol, n-butanol, and any combination thereof. In some embodiments, the fourth solvent is a combination of anhydrous ethanol and tetrahydrofuran. It is a mixed solvent of anhydrous ethanol and tetrahydrofuran in a volume ratio of 1:2.

[0048] In some embodiments, in a fourth solvent, at a temperature of -30 to 50°C (e.g., -10 to 10°C, 0 to 5°C), a second reducing agent is used to reduce m-phthalaldehyde for 2 to 12 hours (e.g., 4 to 8 hours, 6 hours) to obtain crude oily m-hydroxymethylbenzaldehyde, which is then used directly in the next reaction without purification.

[0049] The second aspect of this application provides a compound of formula 3 or a salt thereof.

[0050] Wherein R is a chlorine, bromine, iodine, methanesulfonate group or p-toluenesulfonate group, preferably chlorine, bromine, or iodine, and more preferably bromine.

[0051] A third aspect of this application provides the use of the compound of Formula 3 or a salt thereof in the preparation of the compound of Formula I or a pharmaceutically acceptable salt thereof.

[0052] In this application, the substitution reaction reagent includes halogenated reagents and those reagents that exhibit properties similar to halogenated reagents, such as the HR listed in the embodiments of this application. a CH3S(O)2OR a CF3S(O)2OR aor p -CH3C6H4S(O)2OR a 、S(O)(R a 2. P(R) a 3. P(R) a 5. or , where R a The definition is as described in any embodiment of the first aspect of this application.

[0053] Beneficial effects

[0054] The preparation formula I provided in this application is shown ( S )-2-((3-((benzo[ d The method of [1,3]dioxolane-5-oxo)methyl)benzyl)-amino)propionamide or a pharmaceutically acceptable salt thereof has one or more of the following advantages: a) Using the new compound shown in Formula 3 as an intermediate to prepare the compound shown in Formula 4 significantly improved the reaction rate, reduced the reaction time, and significantly improved the purity of the product, allowing it to proceed directly to the next step of the reaction without post-treatment purification.

[0055] b) Using sodium triacetoxyborohydride or sodium triacetoxyborohydride as the first reducing agent has the following advantages compared to sodium cyanoborohydride used in the method disclosed in CN104761531A: 1) Inexpensive and low-cost; 2) Low toxicity, mild reaction conditions, safe and environmentally friendly; 3) High reaction selectivity, selectively reducing only imines in the reaction, without generating aldehyde reduction products, resulting in pure and easily processed products; 4) Simple operation, suitable for industrial production. Sodium cyanoborohydride, on the other hand, carries the risk of generating free cyano groups, which are highly toxic. Furthermore, when sodium cyanoborohydride is used as a reducing agent to reduce the aldehyde group of the compound shown in Formula 4, it easily generates alcoholic hydroxyl impurities that are difficult to remove.

[0056] c) The method provided in this application has a high overall yield and can be used to prepare compounds of Formula I on a large scale, including kilogram-scale batches. Calculated using the starting material isophthalaldehyde, the overall yield of the method provided in this application is greater than 30%, preferably greater than or equal to 40%, while the overall yield of the method disclosed in CN104761531A is only 19.4%.

[0057] d) The preparation of the new compound shown in Formula 3 is simple, yields high, and is conducive to industrial production. In the preparation process, after the synthesis of m-hydroxymethylbenzaldehyde, only simple separation is required; the resulting oily substance does not need further purification and can be directly used for the next reaction. After the synthesis of m-bromomethylbenzaldehyde, the post-treatment conditions are simple; purification can be achieved by vacuum distillation after washing, resulting in high yields and facilitating industrial production. Detailed Implementation

[0058] The following specific embodiments further illustrate the substantive content of this application. It should be understood that the following embodiments are for illustrative purposes only and are not intended to limit the scope of protection of this application. In the following embodiments, unless specific conditions are specified, conventional conditions or manufacturer recommendations are followed. Raw materials whose manufacturers are not specified are all commercially available conventional products.

[0059] While many of the materials and operating methods used in the following embodiments are well known in the art, this application still describes them in as much detail as possible. It will be apparent to those skilled in the art that, unless otherwise stated, the materials and operating methods used in the following embodiments are well known in the art.

[0060] Example 1: ( S )-2-((3-((benzo[ d Preparation of [1,3]dioxapentane-5-oxo)methyl)benzyl)-amino)propionamide

[0061] Step i: Preparation of m-hydroxymethylbenzaldehyde (2)

[0062] 3.3 kg (24.6 mol, 1 eq) of isophthalaldehyde (1), 16.5 L of anhydrous ethanol, and 30 L of tetrahydrofuran were added to a reaction flask and dissolved by stirring at room temperature. The mixture was then cooled to 0-5 °C in an ice-water bath. 284 g (7.5 mol, 0.3 eq) of sodium borohydride was added in 5 batches, and the mixture was stirred in an ice-water bath for 6 hours. The reaction was monitored by TLC (developing solvent: PE : EA = 2 : 1). After the reaction was complete, 1N hydrochloric acid was added to quench the reaction, and the pH was adjusted to 4. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The filtrate was dissolved in purified water and ethyl acetate, and the mixture was separated. The aqueous phase was extracted three times with ethyl acetate. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain an oily substance, m-hydroxymethylbenzaldehyde (2). This substance was not purified and was used directly in the next reaction.

[0063] MS (ESI) 119.05 [M-OH] + .

[0064] 1 H NMR (600 MHz, DMSO- d 6) d 10.02 (s, 1H), 7.87 (s, 1H), 7.79 (d, J =7.5 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.56 (t, J= 7.5 Hz, 1H), 5.38 (t, J =5.7 Hz, 1H), 4.60 (d, J = 5.5 Hz, 2H).

[0065] Step ii: Preparation of m-bromomethylbenzaldehyde (3)

[0066] The product from step i, 8 L of 48% HBr aqueous solution, and 12.5 L of toluene were added to a reaction flask. The mixture was heated under reflux for 5 hours. After cooling to room temperature, the mixture was separated. The organic phase was washed with 2 L of saturated sodium bicarbonate solution and 2 L of saturated brine. The mixture was concentrated under reduced pressure until no fraction was obtained. The desired product was collected by vacuum distillation (108-112 °C) to obtain a colorless liquid. The product was stored in a refrigerator at 2-8 °C to obtain 1.95 kg of white solid, with a yield of 66.0%.

[0067] MS (ESI) 198.98 [M+H] + .

[0068] 1 H NMR (600 MHz, CDCl3) d 10.17–9.72 (m, 1H), 7.84 (s, 1H), 7.75 (dd, J = 7.6, 1.2 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 4.47 (s, 2H).

[0069] Step iii: 3-(benzo[ d Preparation of [1,3]dioxapentane-5-oxomethyl)benzaldehyde (4)

[0070] 1.27 kg (9.19 mol, 1 eq) of sesamol, 1.83 kg (9.19 mol, 1 eq) of m-bromomethylbenzaldehyde (3), 12 L of tetrahydrofuran, and 4.38 kg (13.4 mol, 1.5 eq) of cesium carbonate were added to the reaction flask and heated to reflux. The reaction was carried out for 3 hours and monitored by TLC (developing solvent: PE : EA = 6 : 1). After the reaction was complete, the mixture was cooled to room temperature and filtered. The filter cake was washed with 2 L of tetrahydrofuran and the filtrate was used directly for the next reaction.

[0071] MS (ESI) 257.08 [M+H] + .

[0072] 1H NMR (600 MHz, CDCl3) d 9.97 (s, 1H), 7.89–7.83 (m, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.62 (dd, J = 7.6, 0.6 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 6.64(d, J = 8.5 Hz, 1H), 6.49 (d, J = 2.5 Hz, 1H), 6.32 (dd, J = 8.5, 2.5 Hz,1H), 5.85 (s, 2H), 4.99 (s, 2H).

[0073] Step iv: Preparation of (S)-2-(3-(benzo[1,3]dioxopentane-5-oxomethyl)benzyl)-amino-propionamide (Formula I)

[0074] 1.48 kg (11.9 mol, 1.3 eq) of L-alanine hydrochloride, 10 L of tetrahydrofuran, and 1.3 kg (12.9 mol, 1.4 eq) of triethylamine were added to the reaction flask with stirring, followed by the addition of 3-(benzo[]] from the previous step. d [1,3]dioxapentane-5-oxomethyl)benzaldehyde (4) reaction solution was reacted with anhydrous sodium sulfate 2.6 kg (18.3 mol, 2 eq), cooled in an ice-water bath and stirred for 1 hour, then added 5.85 kg (27.6 mol, 3 eq) sodium triacetoxyborohydride, and slowly heated to 25~35 °C with stirring for 3 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was cooled in an ice-water bath and stirred, then added 10 L of purified water and 20% sodium hydroxide to adjust the pH to 12 (keeping the internal temperature no higher than 30 °C). Water was added to dissolve the solid, and the mixture was separated. It was extracted with ethyl acetate (25 L × 2 times), washed with 10 L of water and 10 L of brine, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to constant weight. 4 L of ethyl acetate was added and stirred, then 4 L of n-heptane was added and stirred for 1 hour. The mixture was filtered and dried to obtain 2.42 kg of white solid crude product, with a yield of 76.8%.

[0075] 2.4 kg of the crude product and 12 L of acetone were added to a 20 L reactor, heated to reflux, slowly cooled to room temperature, and stirred for 3 hours at 0-10 °C. The mixture was then filtered, washed with cold acetone, and 1.93 kg of white solid was obtained, with a yield of 80.7%.

[0076] The overall yield of this embodiment was 40.9%.

[0077] HRMS (ESI) 329.1497 [M+H] + .

[0078] Formula I 1H NMR spectrum: 1 H NMR (400 MHz, DMSO- d 6) d 9.75 (s, 1H), 9.19 (s, 1H), 7.75–7.15 (m,5H), 6.78 (d, J = 8.5 Hz, 1H), 6.68 (d, J = 2.5 Hz, 1H), 6.42 (dd, J = 8.5,2.5 Hz, 1H), 5.92 (s, 2H), 4.99 (s, 2H), 4.04 (d, J = 17.1 Hz, 2H), 3.75 (d, J = 2.4 Hz, 1H), 1.43 (d, J = 7.0 Hz, 3H). Example 2: Preparation of different reducing agents, alkaline reagents, and reaction solvents ( S )-2-((3-((benzo[ d The effect of [1,3]dioxapentane-5-oxo)methyl)benzyl)-amino)propionamide (Formula I) Referring to the method in step iv of Example 1, the reducing agent, alkaline reagent, and reaction solvent in each scheme in Table 1 below are used instead of the reducing agent, alkaline reagent, and reaction solvent in step iv of Example 1 to prepare ( S )-2-((3-((benzo[ d [1,3] Dioxapentane-5-oxo)methyl)benzyl)-amino)propionamide (Formula I), comparing the effects of each scheme on the preparation.

[0079] Table 1

[0080] The results showed that under the conditions of using tetrahydrofuran or acetonitrile as the reaction solvent, triethylamine or N,N-diisopropylethylamine as the base reagent, and sodium triacetoxyborohydride as the reducing agent, a high yield could be achieved to prepare ( S )-2-((3-((benzo[ d [1,3]dioxopentane-5-oxo)methyl)benzyl)-amino)propionamide (Formula I).

[0081] Example 3: (S )-2-((3-((benzo[ d Preparation of [1,3]dioxapentane-5-oxo)methyl)benzyl)-amino)propionamide

[0082] Step i: Preparation of m-hydroxymethylbenzaldehyde (2)

[0083] 100 g (0.745 mol, 1 eq) of isophthalaldehyde (1), 1200 mL of anhydrous ethanol, and 1800 mL of tetrahydrofuran were added to a reaction flask and stirred at room temperature to dissolve. The mixture was then cooled to 0-5 °C in an ice-water bath. 12.3 g (0.228 mol, 0.3 eq) of potassium borohydride were added in 5 portions. The mixture was stirred in an ice-water bath for 6 hours. After the reaction was complete as monitored by TLC, 1N hydrochloric acid was added to quench the reaction. The pH was adjusted to 4. The filtrate was concentrated under reduced pressure, dissolved in purified water and ethyl acetate, separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure and used directly in the next reaction.

[0084] Step ii: Preparation of m-bromomethylbenzaldehyde (3)

[0085] The product m-hydroxymethylbenzaldehyde (2) from the previous step was dissolved in 300 mL of dichloromethane, and 500 mL of 33% HBr acetic acid solution was slowly added dropwise. The reaction was carried out at room temperature for 8 hours. After the reaction was completed, the solvent was concentrated under reduced pressure, dissolved in ethyl acetate, and the organic phase was washed with saturated sodium bicarbonate until the aqueous phase was neutral. The organic phase was washed with saturated brine, and the organic phase was concentrated under reduced pressure until no fraction was distilled. The desired product was collected by vacuum distillation (108~112 °C) to obtain a colorless liquid. The product was stored in a refrigerator at 2-8 °C to obtain 82.7 g of white solid, with a yield of 56.0%.

[0086] Step iii: 3-(benzo[ d Preparation of [1,3]dioxapentane-5-oxomethyl)benzaldehyde (4)

[0087] Sesamol 13.5 g (97.7 mmol, 0.98 eq), m-bromomethylbenzaldehyde (3) 20 g (100 mmol, 1 eq), N,N-dimethylformamide 80 mL, and cesium carbonate 46 g (140 mmol, 1.4 eq) were added to a reaction flask, heated to 60-80°C, and reacted for 3 hours. The reaction was monitored by TLC (developing solvent: PE : EA = 6 : 1). After the reaction was complete, the mixture was cooled to room temperature, filtered, diluted with 120 mL of water, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, filtered off the desiccant, and concentrated to obtain 21 g of oil, with a yield of 82%, which was directly used in the next reaction.

[0088] Step iv: ( S)-2-((3-((benzo[ d Preparation of [1,3]dioxopentane-5-oxo)methyl)benzyl)-amino)propionamide (Formula I)

[0089] 9.4 g (75.8 mmol, 1.3 eq) of L-alanine hydrochloride, 150 mL of tetrahydrofuran, and 7.7 g (76 mmol, 1.3 eq) of triethylamine were added to a reaction flask with stirring, followed by the addition of 3-(benzo[ d [1,3]dioxapentane-5-oxomethyl)benzaldehyde (4) 15 g (58.6 mmol, 1 eq), added 10 g of anhydrous sodium sulfate, cooled in an ice-water bath and stirred for 1 hour, added 37.2 g (176 mmol, 3.0 eq) of sodium triacetoxyborohydride, stirred slowly with stirring, heated to 25~35 °C, stirred for 3 hours, monitored the reaction by TLC, cooled in an ice-water bath and stirred, added purified water to quench, added 20% sodium hydroxide to adjust the pH to 12, separated, extracted twice with ethyl acetate, washed with water, washed with brine, dried with anhydrous sodium sulfate, filtered, concentrated the filtrate under reduced pressure to constant weight, added 15 mL of ethyl acetate and stirred, added 15 mL of n-heptane and stirred for 1 hour, filtered, dried under vacuum to obtain 12.8 g of white solid crude product, yield 66.8%.

[0090] The overall yield in this embodiment was 30.7%.

[0091] Comparative Example 1: 3-(benzo[ d Preparation of [1,3]dioxapentane-5-oxomethyl)benzaldehyde (4)

[0092] Sesamol 6.9 g (50 mmol, 1 eq), m-bromomethylbenzaldehyde (3) 10 g (50 mmol, 1 eq), N,N-dimethylformamide 100 mL, potassium carbonate 10.7 g (77.5 mmol, 1.5 eq), and potassium iodide 0.5 g were added to a reaction flask, heated to 100 °C for 24 hours, cooled to room temperature, filtered, dissolved in ethyl acetate, washed with 100 mL of water, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, and the product was obtained by column chromatography. The yield was <50%, indicating that a significant amount of m-bromomethylbenzaldehyde (3) remained unreacted.

[0093] Comparative Example 1 used potassium carbonate and potassium iodide instead of cesium carbonate as strong base reagents to prepare 3-(benzo[ d [1,3]dioxapentane-5-oxomethyl)benzaldehyde (4) leads to a decrease in product yield and a longer reaction time, up to 24 hours. In other words, the method in this application uses cesium carbonate as a strong base reagent, which can improve the yield of 3-(benzo[ dThe yield of [1,3]dioxapentane-5-oxomethyl)benzaldehyde (4) can be increased, while the reaction time can be greatly reduced.

[0094] Comparative Example 2: Preparation of m-hydroxymethylbenzaldehyde (2)

[0095] 10 g (74.6 mmol, 1 eq) of isophthalaldehyde (1), 120 mL of anhydrous ethanol, and 180 mL of tetrahydrofuran were added to a reaction flask and stirred at room temperature to dissolve. The mixture was then cooled to 0-5 °C in an ice-water bath. 0.86 g (23 mmol, 0.3 eq) of sodium borohydride were added in 5 portions. The mixture was stirred in an ice-water bath for 6 hours. After the reaction was complete as monitored by TLC, dilute hydrochloric acid was added to quench the reaction and the pH was adjusted to 4. The filtrate was concentrated under reduced pressure and dissolved in 100 mL of purified water and 100 mL of ethyl acetate. The mixture was separated, and the aqueous phase was extracted with 100 mL of ethyl acetate. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was separated by silica gel column chromatography with petroleum ether:ethyl acetate = 3:1 as the eluent. The desired fraction was collected to obtain 9.0 g of oily m-hydroxymethylbenzaldehyde (2), with a yield of 88.4%.

[0096] Comparative Example 2 is a preparation method disclosed in patent CN104761531A, which requires column chromatography for post-processing, making it unsuitable for large-scale synthesis.

[0097] Comparative Example 3: 3-(benzo[ d Preparation of [1,3]dioxapentane-5-oxomethyl)benzaldehyde (4)

[0098] 6.2 g sesamol (45.4 mmol, 1.0 eq), 6.8 g (50.0 mmol, 1.1 eq) m-hydroxymethylbenzaldehyde (2), and 13.0 g (50.0 mmol, 1.1 eq) triphenylphosphine were dissolved in 200 mL tetrahydrofuran. 7.8 mL (50.0 mmol, 1.1 eq) of DEAD was slowly added dropwise under ice bath conditions. The reaction was carried out at room temperature for 10 hours. Then, 2.6 mL (16.6 mmol) of DEAD was added, and the reaction was stopped after another 10 hours at room temperature. The solution was filtered, rotary evaporated, washed with 0.5 N sodium hydroxide solution, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was separated by silica gel column chromatography using petroleum ether:ethyl acetate = 6:1 as the eluent. The desired fraction was collected, yielding 6.7 g of an oily substance, with a yield of 58.1%.

[0099] Comparative Example 3 used m-hydroxymethylbenzaldehyde instead of m-bromomethylbenzaldehyde as the preparation material for 3-(benzo[ dThe intermediate of [1,3]dioxapentane-5-oxomethyl)benzaldehyde (4) leads to a decrease in product yield and a reaction time of more than 20 hours. Triphenylphosphine (PPh3) and diethyl azodicarbonate (DEAD) are also used, which leads to the formation of triphenylphosphine byproducts. Column chromatography is required to remove them, making it unsuitable for large-scale production.

[0100] The method of this application uses m-bromomethylbenzaldehyde as a preform preparation method for 3-(benzo[ d The intermediate of [1,3]dioxapentane-5-oxomethyl)benzaldehyde (4) not only improves the product yield but also avoids the formation of triphenylphosphine byproducts, further simplifying subsequent purification operations and shortening the reaction time.

[0101] Comparative Example 4: ( S )-2-((3-((benzo[ d Preparation of [1,3]dioxopentane-5-oxo)methyl)benzyl)-amino)propionamide (Formula I)

[0102] 2.8 g (24 mmol, 1.2 eq) of L-alanine hydrochloride, 80 mL of anhydrous methanol, and 2 mL of triethylamine were added to a reaction flask, and 3-(benzo[ d [1,3]dioxapentane-5-oxomethyl)benzaldehyde (4) 5.1 g (20 mmol, 1 eq) was added to 2 g of 3A molecular sieve, stirred at room temperature for 1 hour, and 1.0 g (16 mmol, 0.8 eq) of sodium cyanoborohydride was added. The mixture was heated to 40 °C and reacted for 3 hours. The mixture was filtered, concentrated under reduced pressure to remove methanol, dissolved in water, and extracted with 30 mL of ethyl acetate. The aqueous phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography with dichloromethane:anhydrous methanol:ammonia = 80:1:0.1 as the eluent. The desired fraction was collected, yielding 1.78 g of white solid, with a yield of 27.1%. TLC monitoring showed that the reaction solution contained a large amount of aldehyde reduction impurities.

[0103] Comparative Example 4 was prepared using anhydrous methanol as the reaction solvent and sodium cyanoborohydride as the reducing agent. S )-2-((3-((benzo[ d [1,3]dioxopentane-5-oxo)methyl)benzyl)-amino)propionamide, with a yield of only 27.1%, and produces a large amount of aldehyde reduction impurities.

[0104] This application uses tetrahydrofuran or acetonitrile as the reaction solvent and sodium triacetoxyborohydride as the reducing agent, resulting in high reaction selectivity and a significantly improved product yield of over 65%, without generating aldehyde reduction impurities. Furthermore, the low cost and low toxicity of sodium triacetoxyborohydride further reduce the cost of this method, making it more environmentally friendly.

[0105] Although specific embodiments of this application have been described in detail, those skilled in the art will understand that various modifications and substitutions can be made to those details based on all the teachings disclosed, and such changes are all within the scope of protection of this application. The full scope of this application is given by the appended claims and any equivalents.

Claims

1. A method for preparing the compound of formula I or a pharmaceutically acceptable salt thereof, comprising: 1) React the compound shown in Formula 3 with sesamol to produce the compound shown in Formula 4; 2) React the compound shown in Formula 4 with L-propanediol to generate the compound shown in Formula I. Wherein R is a chlorine, bromine, iodine, methanesulfonate group, trifluoromethanesulfonate group or p-toluenesulfonate group, preferably chlorine, bromine or iodine, and more preferably bromine.

2. The method of claim 1, wherein step 1) comprises: The compound shown in Formula 3 is reacted with sesamol in a first solvent and in the presence of a first base reagent to produce the compound shown in Formula 4. The first solvent is selected from water, acetonitrile, tetrahydrofuran, ethanol, methanol, N,N-dimethylformamide, and any combination thereof, preferably tetrahydrofuran or N,N-dimethylformamide; the first base reagent is selected from sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, and N,N-diisopropylethylamine, preferably cesium carbonate. Preferably, the molar ratio of the compound shown in Formula 3 to sesamol is 1:0.8~1.2, for example 1:1; Preferably, the ratio of the compound shown in Formula 3 to the first solvent is 1000 g : 2~50 L solvent; for example, 1000 g : 5~20 L solvent, 1000 g : 10~15 L solvent, or 1000 g : 12 L solvent. Preferably, the molar ratio of the compound shown in Formula 3 to the first base reagent is 1:1~2, for example 1:1.2~1.8, for example 1:1.

5.

3. The method of claim 2, wherein step 1) comprises: The compound shown in Formula 3 is reacted with sesamol in a first solvent and in the presence of a first base reagent at a temperature of 20–120 °C (e.g., 20–80 °C, 25–66 °C) for 0.5–8 hours (e.g., 0.5–4 hours, 1 hour, 2 hours, 3 hours) to produce the compound shown in Formula 4.

4. The method of claim 1, wherein step 2) comprises: The compound shown in Formula 4 is reacted with L-propaneamide in a second solvent in the presence of a first reducing agent and a second base reagent to produce the compound shown in Formula I. The second solvent is selected from acetonitrile, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, toluene, and any combination thereof, preferably acetonitrile or tetrahydrofuran; the first reducing agent is selected from sodium triacetoxyborohydride, potassium triacetoxyborohydride, and any combination thereof; the second base reagent is selected from triethylamine, N,N-diisopropylethylamine, pyridine, sodium carbonate, sodium hydroxide, triethylenediamine, and any combination thereof, preferably triethylamine or N,N-diisopropylethylamine. Preferably, the molar ratio of the compound shown in Formula 4 to L-alanine is 1:0.5~2, for example 1:0.8~1.8, for example 1:1~1.5, for example 1:1.3; Preferably, the ratio of the compound shown in Formula 4 to the second solvent is 1000 g : 4~8 L, for example 1000 g : 6 L; Preferably, the molar ratio of the compound shown in Formula 4 to the first reducing agent is 1:1~5, for example 1:2~4, for example 1:2.5~3.5, for example 1:3; Preferably, the molar ratio of the compound shown in Formula 4 to the second base reagent is 1:0.8~2, for example 1:1~1.8, for example 1:1.2~1.6, for example 1:1.

4.

5. The method of claim 4, wherein step 2) comprises: The compound shown in Formula 4 is reacted with L-alanine in a second solvent in the presence of a first reducing agent and a second base reagent at a temperature of 0–100 °C (e.g., 20–50 °C, 25–35 °C) for 0.5–24 hours (e.g., 0.5–6 hours, 2–5 hours, 3 hours) to produce the compound shown in Formula I.

6. The method according to any one of claims 1-5, wherein step 1) comprises: The compound shown in Formula 3 is reacted with sesamol to produce the compound shown in Formula 4. The reaction solution containing the compound shown in Formula 4 is then used directly in step 2 after removing the insoluble solids.

7. The method according to any one of claims 1-5, further comprising: The m-hydroxymethylbenzaldehyde is reacted with a substitution reagent in a third solvent to produce the compound shown in Formula 3, wherein the third solvent is selected from ethyl acetate, dichloromethane, isopropanol, chloroform, toluene, xylene, n-hexane, and any combination thereof, preferably toluene or dichloromethane; the substitution reagent is HR. a CH3S(O)2OR a CF3S(O)2OR a or p -CH3C6H4S(O)2OR a 、S(O)(R a 2. P(R) a 3. P(R) a 5. or R a It consists of chlorine, bromine, and iodine.

8. The method of claim 7, characterized by one or more of the following features: i) The substitution reaction reagent is HBr, preferably an aqueous solution of HBr or an acetic acid solution of HBr, more preferably a 48% aqueous solution of HBr or a 33% acetic acid solution of HBr; ii) react m-hydroxymethylbenzaldehyde with the substitution reagent in a third solvent at a temperature of 0–140°C (e.g., 20–120°C, 60–80°C) for 2–8 hours (e.g., 2–7 hours, 3–6 hours, 5 hours) to produce the compound shown in Formula 3; iii) The ratio of hydroxymethylbenzaldehyde to the substitution reagent is 1000 g : 1.5~3 L, for example 1000 g : 2 L; iv) The ratio of hydroxymethylbenzaldehyde to the third solvent is 1000 g : 2~4 L, for example 1000 g : 3 L.

9. The method of claim 7, further comprising: The second reducing agent is used to reduce m-phthalaldehyde to produce m-hydroxymethylbenzaldehyde; Preferably, the second reducing agent is used in the fourth solvent to reduce m-phthalaldehyde to generate m-hydroxymethylbenzaldehyde; Preferably, in a fourth solvent, at a temperature of -30 to 50°C (e.g., -10 to 10°C, 0 to 5°C), the second reducing agent is used to reduce m-phthalaldehyde for 2 to 10 hours (e.g., 4 to 8 hours, 5 hours, 6 hours) to generate m-hydroxymethylbenzaldehyde; Preferably, the ratio of isophthalaldehyde to the fourth solvent is 1000 g : 0.5~100 L solvent, for example 1000 g : 10~20 L solvent, for example 1000 g : 14~18 L; Preferably, the molar ratio of isophthalaldehyde to the second reducing agent is 1:0.1~0.5, for example 1:0.2~0.4, for example 1:0.3; Preferably, the second reducing agent is sodium borohydride, potassium borohydride, lithium aluminum hydride, or a borane tetrahydrofuran complex, more preferably sodium borohydride or potassium borohydride, and even more preferably sodium borohydride; Preferably, the fourth solvent is selected from anhydrous ethanol, anhydrous methanol, tetrahydrofuran, ethyl acetate, isopropanol, n-butanol and any combination thereof, preferably a combination of anhydrous ethanol and tetrahydrofuran, and more preferably a mixed solvent of anhydrous ethanol and tetrahydrofuran in a volume ratio of 1:

2. Preferably, in a fourth solvent, at a temperature of -30 to 50°C (e.g., -10 to 10°C, 0 to 5°C), the second reducing agent is used to reduce m-phthalaldehyde for 2 to 12 hours (e.g., 4 to 8 hours, 6 hours) to separate crude oily m-hydroxymethylbenzaldehyde, which is then used directly in the next reaction without purification.

10. The compound shown in Formula 3, Wherein R is a chlorine, bromine, iodine, methanesulfonate group or p-toluenesulfonate group, preferably chlorine, bromine, or iodine, and more preferably bromine.

11. Use of the compound of claim 10 in the preparation of the compound of formula I or a pharmaceutically acceptable salt thereof. 。

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