Preparation method of Aoramidis
By improving the synthesis method of Acoramidis, using inexpensive reagents and optimizing reaction steps, the problems of high cost and long steps in the existing technology have been solved, realizing low-cost and efficient preparation of Acoramidis, which is suitable for industrial production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2026-01-14
- Publication Date
- 2026-04-21
AI Technical Summary
The existing Acoramidis synthesis route uses phosphorus tribromide, which is easily hydrolyzed and corrodes the equipment. Compound F is expensive, and the reaction route is long, resulting in high costs and making it unfavorable for industrial production.
Acoramidis was prepared by a four-step reaction using acetylacetone, 1,3-dibromopropane, a phase transfer catalyst, a base, and an organic solvent, involving nucleophilic substitution, condensation, ring-opening, and aromatic nucleophilic substitution reactions, with the use of inexpensive 4-nitro-3-hydroxybenzoic acid.
It reduces production costs, simplifies synthesis steps, increases yield, and is suitable for industrial production.
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Figure CN121895231A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for preparing Acoramidis. Background Technology
[0002] Abnormal protein interactions and aggregation are a major cause of human degenerative diseases; therefore, targeting protein-protein interaction (PPI) inhibitors has therapeutic value. Currently approved PPI inhibitors are mostly protein-based drugs, such as monoclonal antibodies, which suffer from high cost, injection requirements, and a tendency to trigger immune responses. Developing small molecule inhibitors has become a trend. Acoramidis (CAS: 1446711-81-4) is a transthyretin (TTR) stabilizer developed by Stanford University, primarily used to treat myocardial diseases and transthyretin amyloidosis. The following synthetic route for Acoramidis is disclosed: .
[0003] The above route involves a substitution and hydrolysis reaction of acetylacetone with 1,3-dibromopropane to obtain compound C; compound C reacts with hydrazine hydrate, followed by bromination with phosphorus tribromide to obtain compound E; compound E reacts with compound F in the presence of a base in a polar aprotic organic solvent to obtain compound G. This route uses phosphorus tribromide, which readily hydrolyzes and releases hydrogen bromide, corroding the equipment; compound F is also expensive, increasing costs; furthermore, the synthesized compound G requires further hydrolysis to obtain Acoramidis, making the reaction route quite lengthy. Summary of the Invention
[0004] In view of this, the purpose of this invention is to provide a method for preparing Acoramidis. The preparation method provided by this invention has low cost and fewer synthesis steps, which is more conducive to industrial production.
[0005] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides a method for preparing Acoramidis, comprising the following steps: A mixture of acetylacetone, 1,3-dibromopropane, a first phase transfer catalyst, a base, and a first organic solvent was carried out to undergo a nucleophilic substitution reaction to obtain the compound shown in Formula I. The compound shown in Formula I, hydrazine hydrate, and a second organic solvent are mixed and subjected to a condensation reaction to obtain the compound shown in Formula J. The compound shown in formula J, 4-nitro-3-hydroxybenzoic acid, an acid, and a third organic solvent are mixed and subjected to a ring-opening reaction to obtain the compound shown in formula L. The compound represented by formula L, a fluorinating agent, a second-phase transfer catalyst, and a fourth organic solvent were mixed and subjected to an aromatic nucleophilic substitution reaction to obtain Acoramidis; Formula I, Formula J, Formula L.
[0006] Preferably, the first phase transfer catalyst comprises one or more of 1-butyl-3-methylimidazolium tetrafluoroborate, 1-butyl-3-methylimidazolium hexafluorophosphate, 1-butyl-3-methylimidazolium bromide, and 1-butyl-3-methylimidazolium iodide; the base comprises one or more of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium bicarbonate, and sodium bicarbonate.
[0007] Preferably, the molar ratio of 1,3-dibromopropane to acetylacetone is (1.0~2.0):1, the molar ratio of the first phase transfer catalyst to acetylacetone is (0.05~0.5):1, and the molar ratio of the base to acetylacetone is (1.0~5.0):1.
[0008] Preferably, the nucleophilic substitution reaction is carried out at a temperature of 40-110°C for 2-8 hours.
[0009] Preferably, the molar ratio of the hydrazine hydrate to the compound shown in Formula I is (1.0~5.0):1; the temperature of the condensation reaction is 0~80℃ and the time is 3~10h.
[0010] Preferably, the acid includes one or more of sulfuric acid, p-toluenesulfonic acid, and Lewis acids; the molar ratio of the compound represented by formula J to 4-nitro-3-hydroxybenzoic acid is (0.3~1):1, and the molar ratio of the acid to the compound represented by formula J is (1.0~3.0):1.
[0011] Preferably, the ring-opening reaction is carried out at a temperature of 30~120℃ for 8~20h.
[0012] Preferably, the fluorinating agent includes one or more of potassium fluoride, sodium fluoride, and cesium fluoride; the second phase transfer catalyst includes one or more of tetrabutylammonium fluoride, tetrabutylammonium bromide, and tetrabutylammonium chloride.
[0013] Preferably, the molar ratio of the fluorinating agent to the compound shown in Formula L is (1.0~5.0):1, and the molar ratio of the second phase transfer catalyst to the compound shown in Formula L is (0.01~3.0):1.
[0014] Preferably, the aromatic nucleophilic substitution reaction is carried out at a temperature of 0-120°C for a time of 2-10 hours.
[0015] This invention provides a method for preparing Acoramidis, comprising the following steps: mixing acetylacetone, 1,3-dibromopropane, a first phase transfer catalyst, a base, and a first organic solvent to carry out a nucleophilic substitution reaction to obtain the compound shown in Formula I; mixing the compound shown in Formula I, hydrazine hydrate, and a second organic solvent to carry out a condensation reaction to obtain the compound shown in Formula J; mixing the compound shown in Formula J, 4-nitro-3-hydroxybenzoic acid, an acid, and a third organic solvent to carry out a ring-opening reaction to obtain the compound shown in Formula L; and mixing the compound shown in Formula L, a fluorinating agent, a second phase transfer catalyst, and a fourth organic solvent to carry out an aromatic nucleophilic substitution reaction to obtain Acoramidis. Compared with the prior art, this invention has the following advantages: this invention uses the cheaper reagent 4-nitro-3-hydroxybenzoic acid, which can greatly reduce production costs; this invention optimizes the reaction steps through the construction of a four-membered ring, and Acoramidis can be prepared in four steps: nucleophilic substitution reaction, condensation reaction, ring-opening reaction, and aromatic nucleophilic substitution reaction, resulting in a shorter reaction route. This invention enables the preparation of Acoramidis at a lower cost and with fewer synthesis steps, which is more conducive to industrial production; in addition, the preparation method provided by this invention has a high yield. Attached Figure Description
[0016] Figure 1 The proton nuclear magnetic resonance spectrum of compound I prepared for example; Figure 2 The proton nuclear magnetic resonance spectrum of compound J prepared for the example; Figure 3 The proton nuclear magnetic resonance spectrum of compound L prepared for the example; Figure 4 The hydrogen nuclear magnetic resonance spectrum of Acoramidis prepared as an example. Detailed Implementation
[0017] This invention provides a method for preparing Acoramidis, comprising the following steps: A mixture of acetylacetone, 1,3-dibromopropane, a first phase transfer catalyst, a base, and a first organic solvent was carried out to undergo a nucleophilic substitution reaction to obtain the compound shown in Formula I. The compound shown in Formula I, hydrazine hydrate, and a second organic solvent are mixed and subjected to a condensation reaction to obtain the compound shown in Formula J. The compound shown in formula J, 4-nitro-3-hydroxybenzoic acid, an acid, and a third organic solvent are mixed and subjected to a ring-opening reaction to obtain the compound shown in formula L. The compound represented by formula L, a fluorinating agent, a second-phase transfer catalyst, and a fourth organic solvent were mixed and subjected to an aromatic nucleophilic substitution reaction to obtain Acoramidis; Formula I, Formula J, Formula L.
[0018] Unless otherwise specified, all raw materials involved in this invention are commercially available products well known in the art.
[0019] The reaction formulas involved in the preparation of Acoramidis in this invention are as follows: .
[0020] The following is a detailed explanation.
[0021] In this invention, acetylacetone (compound A), 1,3-dibromopropane, a first phase transfer catalyst, a base, and a first organic solvent are mixed and subjected to a nucleophilic substitution reaction to obtain the compound shown in Formula I (i.e., compound I).
[0022] In this invention, the first phase transfer catalyst preferably comprises one or more of 1-butyl-3-methylimidazolium tetrafluoroborate, 1-butyl-3-methylimidazolium hexafluorophosphate, 1-butyl-3-methylimidazolium bromide, and 1-butyl-3-methylimidazolium iodide, more preferably 1-butyl-3-methylimidazolium tetrafluoroborate; the base preferably comprises one or more of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium bicarbonate, and sodium bicarbonate, more preferably potassium carbonate or sodium carbonate. In this invention, the molar ratio of 1,3-dibromopropane to acetylacetone is preferably (1.0~2.0):1, more preferably (1.5~1.8):1; the molar ratio of the first phase transfer catalyst to acetylacetone is preferably (0.05~0.5):1, more preferably (0.05~0.15):1, and can be (0.1~0.11):1; the molar ratio of the base to acetylacetone is preferably (1.0~5.0):1, more preferably (1.0~3.0):1, and can be 1.0:1 or 1.1:1. In this invention, the first organic solvent is preferably one or more of DMF, DMAc, DMSO, THF, N-methylpyrrolidone, acetone, and acetonitrile, more preferably DMF or DMSO; this invention does not have special requirements for the amount of the first organic solvent, as long as the dissolution of the raw materials and the smooth progress of the reaction are ensured.
[0023] In this invention, the temperature of the nucleophilic substitution reaction is preferably 40~110℃, more preferably 60~100℃, and can be 60 or 70℃, and the time is preferably 2~8h, and can be 3~5h.
[0024] After the nucleophilic substitution reaction is completed, the present invention preferably performs post-treatment on the obtained reaction solution. The preferred method of post-treatment is as follows: the reaction solution obtained from the nucleophilic substitution reaction is poured into a mixture of water and dichloromethane, and the mixture is stirred, allowed to stand, separated, and the lower layer is removed and rotary evaporated to obtain the compound shown in Formula I (yellow oily liquid); the volume ratio of water to dichloromethane is preferably 10:1; the stirring time can be 10 min.
[0025] After obtaining the compound shown in Formula I, the present invention mixes the compound shown in Formula I, hydrazine hydrate, and a second organic solvent to carry out a condensation reaction to obtain the compound shown in Formula J (i.e., compound J).
[0026] In this invention, the molar ratio of hydrazine hydrate to the compound shown in Formula I is preferably (1.0~5.0):1, more preferably (1.0~1.5):1, and can be (1.0~1.1):1. In this invention, the second organic solvent preferably includes one or more of methanol, ethanol, isopropanol, THF, and acetonitrile, more preferably methanol or THF. This invention does not have particular requirements on the amount of the second organic solvent used, as long as the dissolution of the raw materials and the smooth progress of the reaction are ensured.
[0027] In this invention, the temperature of the condensation reaction is preferably 0~80℃, more preferably 20~30℃. In embodiments of this invention, the condensation reaction is carried out at room temperature (i.e., no additional heating or cooling is required). The time of the condensation reaction is preferably 3~10h, more preferably 4~6h, and can be 5h. In this invention, the condensation reaction is preferably carried out under stirring conditions.
[0028] After the condensation reaction is completed, the present invention preferably performs post-treatment on the obtained reaction solution; the preferred method of post-treatment is to pour the reaction solution obtained from the condensation reaction into a mixture of water and dichloromethane, stir, separate the liquids, and remove the lower layer by rotary evaporation to obtain the compound (yellow liquid) shown in formula J; the volume ratio of water to dichloromethane is preferably 3:1, and the stirring time can be 15 min.
[0029] After obtaining the compound shown in Formula J, the present invention mixes the compound shown in Formula J, 4-nitro-3-hydroxybenzoic acid (compound K), an acid and a third organic solvent to carry out a ring-opening reaction to obtain the compound shown in Formula L (i.e., compound L).
[0030] In this invention, the acid preferably includes one or more of sulfuric acid (H2SO4), p-toluenesulfonic acid, and Lewis acids (which may be AlCl3 or BF3·Et2O), more preferably p-toluenesulfonic acid. In this invention, the molar ratio of the compound represented by formula J to 4-nitro-3-hydroxybenzoic acid is preferably (0.3~1):1, and can be (0.8~1):1; the molar ratio of the acid to the compound represented by formula J is preferably (1.0~3.0):1, more preferably (1.2~1.8):1. In this invention, the 4-nitro-3-hydroxybenzoic acid is inexpensive, thereby reducing production costs. In this invention, the third organic solvent is preferably one or more of DMF, DMAc, DMSO, MeCN, and THF, more preferably DMF or THF; this invention does not have special requirements for the amount of the third organic solvent used, as long as the dissolution of the raw materials and the smooth progress of the reaction are ensured.
[0031] In this invention, the preferred method for mixing the compound represented by formula J, 4-nitro-3-hydroxybenzoic acid (compound K), the acid, and the third organic solvent is as follows: The compound represented by formula J, the acid, and the third organic solvent are added to a reaction vessel, stirred for 15 min, and then cooled in an ice-water bath; subsequently, 4-nitro-3-hydroxybenzoic acid is added to the resulting system. In this invention, the 4-nitro-3-hydroxybenzoic acid is preferably added dropwise in the form of a 4-nitro-3-hydroxybenzoic acid solution, and the solvent in the 4-nitro-3-hydroxybenzoic acid solution is preferably the same as the third organic solvent; during the dropwise addition, the temperature of the system preferably does not exceed 5°C.
[0032] In this invention, the ring-opening reaction temperature is preferably 30~120℃ (more preferably 50~70℃, and can be 60℃); the temperature of the mixed system after the addition of 4-nitro-3-hydroxybenzoic acid is raised to 30~120℃ to carry out the ring-opening reaction; the ring-opening reaction time is preferably 8~20h, preferably 10~16h, and can be 15h; the ring-opening reaction is preferably carried out under stirring conditions.
[0033] After the ring-opening reaction is completed, the present invention preferably performs post-treatment on the obtained reaction solution; the preferred method of post-treatment is as follows: water is added to the reaction solution obtained from the ring-opening reaction to quench the reaction, then dichloromethane is added for extraction, the lower layer is taken off and dried by rotary evaporation, dichloromethane is added, the mixture is stirred, then n-hexane is added dropwise, and then the mixture is cooled in an ice-water bath to precipitate a white solid. After solid-liquid separation (such as vacuum filtration), the compound shown in formula L (white compound) is obtained.
[0034] After obtaining the compound shown in Formula L, the present invention mixes the compound shown in Formula L, a fluorinating agent, a second phase transfer catalyst and a fourth organic solvent to carry out an aromatic nucleophilic substitution reaction to obtain Acoramidis (compound H).
[0035] In this invention, the fluorinating agent preferably includes one or more of potassium fluoride, sodium fluoride, and cesium fluoride, more preferably potassium fluoride or sodium fluoride; the second phase transfer catalyst preferably includes one or more of tetrabutylammonium fluoride, tetrabutylammonium bromide, and tetrabutylammonium chloride, more preferably tetrabutylammonium fluoride. In this invention, the molar ratio of the fluorinating agent to the compound shown in Formula L is preferably (1.0~5.0):1, more preferably (1.0~2.0):1, and can be 1.0:1 or 1.1:1; the molar ratio of the second phase transfer catalyst to the compound shown in Formula L is preferably (0.01~3.0):1, more preferably (0.05~1.50):1, and can be 0.3:1. In this invention, the fourth organic solvent is preferably one or more of acetonitrile, DMSO, DMF, THF, dichloromethane, ethyl acetate, and acetone, more preferably acetonitrile or DMSO; this invention does not have special requirements for the amount of the fourth organic solvent, as long as the dissolution of the raw materials and the smooth progress of the reaction are ensured.
[0036] In this invention, the temperature of the aromatic nucleophilic substitution reaction is preferably 0~120℃, more preferably 10~80℃, and can be 20~40℃; the time is preferably 2~10h, more preferably 2~5h; the aromatic nucleophilic substitution reaction is preferably carried out under stirring conditions.
[0037] After the aromatic nucleophilic substitution reaction is completed, the present invention preferably performs post-treatment on the resulting reaction solution. The preferred post-treatment method is as follows: the reaction solution obtained from the aromatic nucleophilic substitution reaction is poured into water, extracted with ethyl acetate, and the resulting organic phase is successively washed with water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain a crude product; the crude product is then slurried with n-heptane to obtain a white solid compound, namely Acoramidis. In the present invention, the ethyl acetate extraction is preferably performed three times, and the organic phases are combined.
[0038] This invention provides a simple method for preparing Acoramidis. The preparation method provided by this invention uses low-cost raw materials and reduces the number of synthesis steps, thereby greatly reducing production costs and making it more conducive to industrial production.
[0039] To further illustrate the present invention, the preparation method of Acoramidis provided by the present invention will be described in detail below with reference to examples, but these should not be construed as limiting the scope of protection of the present invention.
[0040] Example 1 The preparation of compound I is carried out according to the following reaction formula: .
[0041] Method 1: Compound A (20.02 g, 200 mmol), 1,3-dibromopropane (60.57 g, 300 mmol), potassium carbonate powder (27.64 g, 200 mmol), 1-butyl-3-methylimidazolium tetrafluoroborate (4.52 g, 20 mmol), and DMF (400 mL) were added to a reaction flask, and the mixture was heated to 60 °C and reacted for 5 h. The mixture was then poured into a mixture containing 2000 mL of water and 200 mL of dichloromethane, stirred for 10 min, allowed to stand, separated, and the lower layer was removed and rotary evaporated to obtain 25.23 g of yellow oily liquid (compound I), with a yield of 90%. 1 H NMR (400 MHz, Chloroform- d ) δ 2.97(t, J = 8.0 Hz, 4H), 2.10(s, 6H), 1.94–1.86(m, 2H). Figure 1 The hydrogen nuclear magnetic resonance spectrum of compound I is shown.
[0042] Method 2: Compound A (20.02 g, 200 mmol), 1,3-dibromopropane (72.68 g, 360 mmol), sodium carbonate powder (23.32 g, 220 mmol), 1-butyl-3-methylimidazolium tetrafluoroborate (4.52 g, 20 mmol), and DMSO (400 mL) were added to a reaction flask, and the mixture was heated to 70 °C and reacted for 3 h. The mixture was then poured into a mixture containing 2000 mL of water and 200 mL of dichloromethane, stirred for 10 min, allowed to stand, separated, and the lower layer was removed and rotary evaporated to obtain 24.67 g of a yellow oily liquid (compound I), with a yield of 88%.
[0043] Example 2 The preparation of compound J follows the reaction formula below: .
[0044] Method 1: 7.01 g of compound I (50 mmol), 100 mL of methanol and 3.25 g (80% content, 52 mmol) of hydrazine hydrate were added to a reaction flask and stirred at room temperature for 5 h. The mixture was then poured into a mixture containing 300 mL of water and 100 mL of dichloromethane and stirred for 15 min. The mixture was separated into layers, the lower layer was collected, and the solution was evaporated to dryness to obtain 5.45 g of yellow liquid (compound J), with a yield of 80%. 1 H NMR (400MHz, Chloroform- d ) δ 2.93(t, J= 8.0 Hz, 4H), 2.01(s, 6H), 1.90–1.82(m, 2H). Figure 2 The hydrogen nuclear magnetic resonance spectrum of the prepared compound J is shown.
[0045] Method 2: 7.01 g of compound I (50 mmol), 100 mL of THF and 3.44 g (80% content, 55 mmol) of hydrazine hydrate were added to a reaction flask. The mixture was stirred at room temperature for 5 h. The mixture was then poured into a mixture containing 300 mL of water and 100 mL of dichloromethane and stirred for 15 min. The mixture was separated into layers, the lower layer was removed, and the solution was evaporated to dryness to obtain 5.11 g of yellow liquid (compound J), with a yield of 75%.
[0046] Example 3 The preparation of compound L follows the reaction formula: .
[0047] Method 1: Add 6.81 g (50 mmol) of compound J, 10.33 g (60 mmol) of p-toluenesulfonic acid, and 100 mL of DMF to a reaction flask, stir for 15 min, cool in an ice-water bath, and add 10.99 g (60 mmol) of compound K (dissolved in 30 mL of DMF) dropwise, with the temperature not exceeding 5 °C during the dropwise addition; after the dropwise addition is complete, gradually raise the temperature to 60 °C, stir for 15 h, add water (100 mL) to quench the reaction, add dichloromethane (50 mL), extract, take the lower layer, evaporate to dryness, add 20 mL of dichloromethane, stir for 5 min, add 100 mL of n-hexane dropwise, cool in an ice-water bath, and a large amount of white solid precipitates. Filter to obtain 12.13 g of white product (compound L), yield 76%. 1 H NMR (400 MHz, Methanol- d 4) δ 7.70–7.62 (m,2H), 7.22-7.18 (m, 1H), 4.10 (t, J = 5.8 Hz, 2H), 2.74 (t, J = 7.3 Hz, 2H), 2.35 (s, 6H), 2.12-1.99 (m, 2H). Figure 3 The hydrogen nuclear magnetic resonance spectrum of the prepared compound L is shown.
[0048] Method 2: Add 6.81 g (50 mmol) of compound J, 10.33 g (60 mmol) of p-toluenesulfonic acid, and 100 mL of THF to a reaction flask, stir for 15 min, cool in an ice-water bath, and add 10.99 g (60 mmol) of compound K (dissolved in 30 mL of THF) dropwise, with the temperature not exceeding 5 °C during the dropwise addition; after the dropwise addition is complete, gradually raise the temperature to 60 °C, stir for 15 h, add water (100 mL) to quench the reaction, add dichloromethane (50 mL), extract, take the lower layer, evaporate to dryness, add 20 mL of dichloromethane, stir for 5 min, add 100 mL of n-hexane dropwise, cool in an ice-water bath, and a large amount of white solid precipitates. Filter to obtain 11.18 g of white product (compound L), yield 70%.
[0049] Example 4 The preparation of compound H (Acoramidis) follows the reaction formula below: .
[0050] Method 1: Add 9.58 g (30 mmol) of compound L, 1.26 g (30 mmol) of sodium fluoride, 9.0 mL (1 mol / L THF solution, 9 mmol) of tetrabutylammonium fluoride and 50 mL of acetonitrile to a reaction flask, heat to 40 °C and stir for 2 h; pour into 300 mL of water, extract three times with 100 mL of ethyl acetate each time, combine the organic phases, wash once with 30 mL of water, dry with anhydrous sodium sulfate, filter, evaporate to dryness, and beat the crude product with n-heptane to give 8.07 g of white solid product (compound H), yield 92%. 1 HNMR (400 MHz, DMSO- d 6) δ 14.07(s, 1H), 7.62-7.59 (m, 1H), 7.58-7.54 (m, 1H), 7.36-7.31 (m, 1H), 4.05 (t, J = 6.1 Hz, 2H), 2.57–2.51 (m, 2H), 2.19 (s, 6H), 1.95–1.84 (m, 2H). Figure 4 The hydrogen nuclear magnetic resonance spectrum of the prepared Acoramidis.
[0051] Method 2: Add 9.58 g (30 mmol) of compound L, 1.92 g (33 mmol) of potassium fluoride, 8.0 mL (1 mol / L THF solution, 8 mmol) of tetrabutylammonium fluoride and 60 mL of DMSO to a reaction flask, and stir at room temperature for 2 h; pour into 300 mL of water, extract three times with 100 mL of ethyl acetate each time, combine the organic phases, wash once with 30 mL of water, dry with anhydrous sodium sulfate, filter, evaporate to dryness, and beat the crude product with n-heptane to give 7.45 g of white solid product (compound H), yield 85%.
[0052] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.
Claims
1. A method for preparing Acoramidis, characterized in that, Includes the following steps: A mixture of acetylacetone, 1,3-dibromopropane, a first phase transfer catalyst, a base, and a first organic solvent was carried out to undergo a nucleophilic substitution reaction to obtain the compound shown in Formula I. The compound shown in Formula I, hydrazine hydrate, and a second organic solvent are mixed and subjected to a condensation reaction to obtain the compound shown in Formula J. The compound shown in formula J, 4-nitro-3-hydroxybenzoic acid, an acid, and a third organic solvent are mixed and subjected to a ring-opening reaction to obtain the compound shown in formula L. The compound represented by formula L, a fluorinating agent, a second-phase transfer catalyst, and a fourth organic solvent were mixed and subjected to an aromatic nucleophilic substitution reaction to obtain Acoramidis; Formula I, Formula J, Formula L.
2. The preparation method according to claim 1, characterized in that, The first phase transfer catalyst comprises one or more of 1-butyl-3-methylimidazolium tetrafluoroborate, 1-butyl-3-methylimidazolium hexafluorophosphate, 1-butyl-3-methylimidazolium bromide, and 1-butyl-3-methylimidazolium iodide; the base comprises one or more of potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium bicarbonate, and sodium bicarbonate.
3. The preparation method according to claim 1 or 2, characterized in that, The molar ratio of 1,3-dibromopropane to acetylacetone is (1.0~2.0):1, the molar ratio of the first phase transfer catalyst to acetylacetone is (0.05~0.5):1, and the molar ratio of the base to acetylacetone is (1.0~5.0):
1.
4. The preparation method according to claim 1, characterized in that, The nucleophilic substitution reaction is carried out at a temperature of 40~110℃ for a time of 2~8h.
5. The preparation method according to claim 1, characterized in that, The molar ratio of the hydrazine hydrate to the compound shown in Formula I is (1.0~5.0):1; the temperature of the condensation reaction is 0~80℃ and the time is 3~10h.
6. The preparation method according to claim 1, characterized in that, The acid includes one or more of sulfuric acid, p-toluenesulfonic acid, and Lewis acids; the molar ratio of the compound represented by formula J to 4-nitro-3-hydroxybenzoic acid is (0.3~1):1, and the molar ratio of the acid to the compound represented by formula J is (1.0~3.0):
1.
7. The preparation method according to claim 1 or 6, characterized in that, The ring-opening reaction is carried out at a temperature of 30~120℃ for 8~20h.
8. The preparation method according to claim 1, characterized in that, The fluorinating agent includes one or more of potassium fluoride, sodium fluoride, and cesium fluoride; the second phase transfer catalyst includes one or more of tetrabutylammonium fluoride, tetrabutylammonium bromide, and tetrabutylammonium chloride.
9. The preparation method according to claim 1 or 8, characterized in that, The molar ratio of the fluorinating agent to the compound shown in Formula L is (1.0~5.0):1, and the molar ratio of the second phase transfer catalyst to the compound shown in Formula L is (0.01~3.0):
1.
10. The preparation method according to claim 1, characterized in that, The aromatic nucleophilic substitution reaction is carried out at a temperature of 0~120℃ for a time of 2~10h.