Preparation method of Aficamten

Abstract

The invention discloses a preparation method of Aficamten and a preparation method of the Aficamten. The preparation method comprises the following steps: by taking 5-cyano-1-indanone as a starting material, carrying out carbonyl protection, then reacting with hydroxylamine hydrochloride, then sequentially carrying out cyclization, deprotection and Noyori asymmetric hydrogenation to obtain a chiral intermediate, then carrying out Mitsunobu reaction on the chiral intermediate and phthalimide, and then carrying out hydrolysis and condensation to obtain the chiral intermediate. The route provides a preparation method of Aficamten, which is simple, easy to operate and suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the field of medicinal chemistry, and particularly relates to a preparation method of Aficamten. Background Art

[0002] Aficamten is a cardiac myosin inhibitor that can alleviate the symptoms of heart failure, improve exercise capacity and NYHA heart function class. The drug was independently developed by the biotechnology company Cytokinetics. In July 2020, Jixing Pharmaceutical obtained exclusive licensing rights to develop and commercialize Aficamten in Greater China. In 2022, Aficamten was included in the breakthrough therapy designation by CDE for the treatment of obstructive HCM (oHCM). As a second-generation cardiac myosin inhibitor, Aficamten has similar pharmacological effects to mavacamten, but has a shorter half-life, can be titrated once every two weeks, and blood concentrations can reach steady state in a short time. In addition, Aficamten has a lower dose-effect curve, giving it a wider therapeutic window. Aficamten's chemical name is (R)-N-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-4-carboxamide. Its chemical structure is as follows:

[0003]

[0004] The Chinese patent CN111757875A reports the synthesis route of Aficamten, which is as follows:

[0005] Route 1:

[0006]

[0007] This route uses (R)-5-bromo-2,3-dihydro-1H-inden-1-amine as the starting material. Its amino group is protected with a tert-butyloxycarbonyl group and then condensed with potassium ferricyanide to produce a cyanide. This cyanide is then reacted sequentially with hydroxylamine and propionic anhydride to produce an oxadiazole intermediate. Finally, deprotection and amide condensation yield Aficamten. The production process utilizes the expensive XantPhos catalyst, resulting in high production costs and unsuitable for industrial production. Furthermore, potassium ferricyanide is used in the process, which easily decomposes to produce the toxic reagent hydrocyanic acid. This poses certain risks during production and subsequent waste treatment, potentially leading to safety accidents.

[0008] Route 2:

[0009]

[0010] Starting with 5-bromoindanone, a chiral amine intermediate is obtained through chiral reduction, azidation with diphenylphosphoryl azide (DPPA), and tin chloride reduction. After protection with a tert-butyloxycarbonyl group, the chiral amine intermediate is condensed with potassium ferricyanide to obtain a cyanide. This cyanide is then reacted sequentially with hydroxylamine and propionic anhydride to obtain an oxadiazole intermediate. Finally, deprotection and amide condensation yield Aficamten. This reaction also suffers from the same issues as Route 1. The expensive XantPhos catalyst is used in the production process, resulting in high production costs and unfavorable for scalable production. Furthermore, potassium ferricyanide is used in the production process, which easily decomposes to produce the toxic reagent hydrocyanic acid. This poses certain risks during production and subsequent waste treatment, and can easily lead to safety accidents.

[0011] Therefore, there is an urgent need to develop a method for preparing Aficamten with a simple reaction process, mild conditions, simple and safe post-treatment, environmental friendliness, high total yield, low production cost, and suitability for industrial large-scale production. Summary of the Invention

[0012] In view of the shortcomings of the prior art, the object of the present invention is to provide a method for preparing Aficamten that is simple, easy to operate and suitable for industrial production.

[0013] The present invention uses 5-cyano-1-indanone as the starting material, which is reacted with hydroxylamine hydrochloride after carbonyl protection to obtain intermediate compound 3. The chiral intermediate compound 6 is then subjected to cyclization, deprotection, and Noyori asymmetric hydrogenation. The chiral intermediate compound 6 is then subjected to a Mitsunobu reaction with phthalimide and hydrolyzed to obtain a chiral amine intermediate compound 8. Finally, Aficamten is prepared through condensation. Specifically, the objectives of the present invention are achieved through the following technical solutions:

[0014] S1: Compound 1 reacts with ethylene glycol in the presence of an acidic reagent to obtain intermediate compound 2;

[0015] S2: Intermediate compound 2 and hydroxylamine hydrochloride are reacted with an alkaline reagent to prepare intermediate compound 3;

[0016] S3: Intermediate compound 3 undergoes a cyclization reaction with propionic anhydride at a certain reaction temperature to prepare intermediate compound 4;

[0017] S4: Intermediate compound 4 undergoes hydrolysis reaction in an organic solvent under acidic conditions to prepare intermediate compound 5;

[0018] S5: Intermediate compound 5 undergoes Noyori asymmetric hydrogenation reaction in the presence of a chiral catalyst to prepare intermediate compound 6;

[0019] S6: Intermediate compound 6 undergoes Mitsunobu reaction with phthalimide to prepare intermediate compound 7;

[0020] S7: Intermediate compound 7 undergoes hydrazine hydrolysis reaction under the action of hydrazine hydrate to prepare intermediate compound 8;

[0021] S8: The intermediate compound 8 undergoes a condensation reaction with 1-methyl-1H-pyrazole-4-carboxylic acid to prepare the target product Aficamten;

[0022] The reaction route is as follows:

[0023]

[0024] As a specific embodiment, the acidic reagent in step S1 is p-toluenesulfonic acid, and the molar ratio of compound 1 to the acidic reagent is 5:1 to 2:1;

[0025] As a preference, the molar ratio of compound 1 to the acidic reagent in step S1 is 3:1.

[0026] As a specific embodiment, after the reaction of step S1 is completed, post-treatment is performed, specifically: the reaction solution is cooled to room temperature, concentrated to dryness under reduced pressure, ethyl acetate and water are added, and the organic phase is separated and retained; the organic phase is washed with saturated sodium bicarbonate and saturated brine in sequence, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to remove the organic solvent, and purified by silica gel column chromatography to obtain intermediate compound 2.

[0027] As a specific embodiment, the alkaline reagent in step S2 is one of sodium bicarbonate, sodium carbonate, potassium carbonate, and sodium hydroxide; the molar ratio of the intermediate compound 2 to hydroxylamine hydrochloride is 1:4 to 1:8, preferably 1:5 to 1:6.

[0028] As a specific embodiment, after the reaction of step S2 is completed, post-treatment is performed. Specifically, the reaction solution is cooled to room temperature, extracted three times with dichloromethane, the organic phase is washed with water and saturated brine, dried over sodium sulfate, and then concentrated under reduced pressure to remove the organic solvent, and purified by silica gel column chromatography to obtain the intermediate compound 3.

[0029] As a specific embodiment, the cyclization reaction temperature in step S3 is 60-80° C., and the molar ratio of the intermediate compound 3 to propionic anhydride is 1:1.1-1:5, preferably 1:1.5.

[0030] As a specific embodiment, after the reaction in step S3 is completed, post-treatment is performed, specifically: cooling to room temperature, concentrating under reduced pressure to remove the organic solvent, adding ethyl acetate and water, stirring and layering, extracting the aqueous phase twice with ethyl acetate, retaining the organic phase, washing the organic phase with saturated sodium bicarbonate and saturated brine, drying over anhydrous sodium sulfate, concentrating under reduced pressure to remove the organic solvent, and purifying by silica gel column chromatography to obtain intermediate compound 4.

[0031] As a specific embodiment, the organic solvent in step S4 is one of dichloromethane, ethyl acetate, and 1,4-dioxane, the reaction temperature is room temperature, and the acidic reagent used is dilute hydrochloric acid with a concentration of 1 to 3 mol / L, preferably 2 mol / L.

[0032] As a specific embodiment, after the reaction of step S4 is completed, post-treatment is performed, specifically: concentrating under reduced pressure to remove the organic solvent, adding ethyl acetate and water, stirring and layering, extracting the aqueous phase three times with ethyl acetate, retaining the organic phase, washing the organic phase with saturated sodium bicarbonate and saturated brine, drying over anhydrous sodium sulfate, concentrating under reduced pressure to remove the organic solvent, and purifying by silica gel column chromatography to obtain the intermediate compound 5.

[0033] As a specific embodiment, the chiral catalyst in step S5 is (R)-5,5-biphenyl-2-methyl-3,4-propanol-1,3,2-oxazolidinone, and the molar ratio of the intermediate compound 5 to (R)-5,5-biphenyl-2-methyl-3,4-propanol-1,3,2-oxazolidinone is 5:1 to 10:1, preferably 6.6:1.

[0034] As a specific embodiment, after the reaction of step S5 is completed, post-treatment is performed, specifically: water is added to quench the reaction, extracted three times with ethyl acetate at low temperature, the organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to remove the organic solvent, and purified by silica gel column chromatography to obtain the chiral intermediate compound 6.

[0035] As a specific embodiment, the organic solvent in step S6 is one of tetrahydrofuran, dichloromethane, and acetonitrile, the coupling reagent is one of diethyl azodicarboxylate, diisopropyl azodicarboxylate, and di-tert-butyl azodicarboxylate, and the molar ratio of the intermediate compound 6 to the coupling reagent is 1:1 to 1:5, preferably 1:1 to 1:1.2, and the reaction is a room temperature reaction.

[0036] As a specific embodiment, after the reaction of step S6 is completed, post-treatment is performed, specifically: a small amount of water is added to quench the reaction, extracted three times with ethyl acetate, the organic phase is washed once with saturated brine, dried over anhydrous sodium sulfate, and then the organic solvent is removed under reduced pressure, and purified by silica gel column chromatography to obtain intermediate compound 7.

[0037] As a specific embodiment, the reaction temperature in step S7 is 40-60° C., and the molar ratio of the intermediate compound 7 to hydrazine hydrate is 1:8-1:20, preferably 1:10.

[0038] As a specific embodiment, after the reaction of step S7 is completed, post-treatment is performed, specifically: filtration, concentration of the filtrate to dryness under reduced pressure, and purification by silica gel column chromatography to obtain the intermediate compound 8.

[0039] As a specific embodiment, the condensing agent in step S8 is one or more of N,N-diisopropylethylamine (DIPEA), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBT), and thionyl chloride (SOCl2), and the molar ratio of the intermediate to the condensing agent is:

[0040] Intermediate compound 8: DIPEA:EDCI:HOBT=1:1:1.5:0.2

[0041] Intermediate compound 8: SOCl2=1:2-3

[0042] As a specific embodiment, after the reaction in step S8 is completed, post-treatment is performed. Specifically, ammonium chloride is added to the reaction solution to quench the reaction, the liquid is separated, and the organic phase is retained. The organic phase is washed with saturated sodium bicarbonate and saturated brine in sequence, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography to obtain the target product Aficamten.

[0043] The advantages of the present invention are:

[0044] The new route has a simple reaction process, does not involve dangerous operations such as high temperature and high pressure, is easy to operate, and is easy to industrialize. The reagents involved are all conventional chemical reagents that are easy to obtain, and the target product is obtained in medium to good yields in each step. DETAILED DESCRIPTION

[0045] The synthetic route of Aficamten of the present invention is as follows:

[0046]

[0047] The present invention will be described in detail below with reference to the examples. The following examples will help those skilled in the art to further understand the present invention, but are not intended to limit the present invention in any form. It should be noted that those skilled in the art may make several adjustments and improvements without departing from the scope of the present invention. These all fall within the scope of protection of the present invention.

[0048] Example 1: Preparation of 2,3-dihydrospiro[indene-1,2'-[1,3]dioxolane]-5-carbonitrile (2)

[0049]

[0050] In a three-necked flask, 1-oxo-2,3-dihydro-1H-indene-5-carbonitrile (1) (50 g, 318.1 mmol), toluene (1500 mL), ethylene glycol (39.5 g, 636.2 mmol), and p-toluenesulfonic acid (16.4 g, 95.4 mmol) were added. The mixture was stirred, heated to reflux, and kept warm for overnight reaction. The mixture was cooled, concentrated to dryness under reduced pressure, and ethyl acetate and water were added. The mixture was stirred, separated, and the organic phase was retained. The aqueous phase was extracted twice with ethyl acetate. The organic phases were combined, washed with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The intermediate compound (2) (54.2 g, yield 84.7%) was obtained by silica gel column chromatography. LC-MS: m / z = 202 [M+H] + .

[0051] Example 2: Preparation of N-hydroxy-2,3-dihydrospiro[indene-1,2'-[1,3]dioxolane]-5-carboximide (3)

[0052]

[0053] Method 1: To a three-necked flask, hydroxylamine hydrochloride (93.2 g, 1.3 mol), sodium bicarbonate (112.7 g, 1.34 mol), and purified water (1000 mL) were added in sequence, stirred, and dissolved; a solution of 2,3-dihydrospiro[indene-1,2'-[1,3]dioxolane]-5-carbonitrile (2) (45 g, 223.6 mmol) in ethanol (1200 mL) was added dropwise. After the addition was complete, the temperature was raised to 60°C and kept for reaction for 5 hours; the temperature was lowered to room temperature, and dichloromethane was added for extraction three times. The organic phases were combined, washed with water and saturated brine in sequence, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain the intermediate compound (3) (32.3 g, yield 61.7%), which was directly used in the next step. LC-MS: m / z = 235 [M+H] + .

[0054] Method 2: To a three-necked flask, hydroxylamine hydrochloride (4.1 g, 59.6 mmol), sodium carbonate (4.2 g, 39.8 mmol), and purified water (40 mL) were added in sequence, stirred, and dissolved; a solution of 2,3-dihydrospiro[indene-1,2'-[1,3]dioxolane]-5-carbonitrile (2) (2 g, 9.94 mmol) in ethanol (50 mL) was added dropwise, and after the addition was complete, the temperature was raised to 60°C and the reaction was kept overnight; after the reaction was completed, the temperature was lowered to room temperature, and dichloromethane was added for extraction three times. The organic phases were combined, washed with water and saturated brine in sequence, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain the intermediate compound (3) (1.3 g, yield 55.8%).

[0055] Example 3: Preparation of 3-(2,3-dihydrospiro[indene-1,2'-[1,3]dioxolane]-5-yl)-5-ethyl-1,2,4-oxadiazole (4)

[0056]

[0057] To a three-necked flask were added N-hydroxy-2,3-dihydrospiro[indene-1,2'-[1,3]dioxolane]-5-carboximide (3) (28 g, 119.5 mmol), 1,4-dioxane (600 mL), and propionic anhydride (23.3 g, 179.3 mmol) in sequence, stirred, heated to 80°C, and kept warm for reaction overnight; cooled to room temperature, concentrated under reduced pressure to remove the solvent, ethyl acetate and water were added to the concentrated residue, stirred, and separated, the aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, washed once with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The intermediate compound (4) (21.4 g, yield 65.7%) was obtained by purification by silica gel column chromatography, LCMS: m / z=273[M+H]+.

[0058] Example 4: Preparation of 5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-one (5)

[0059]

[0060] In a three-necked flask, 3-(2,3-dihydrospiro[indene-1,2'-[1,3]dioxolane]-5-yl)-5-ethyl-1,2,4-oxadiazole (4) (18 g, 66.1 mmol) and tetrahydrofuran (540 mL) were added in sequence, and 2 mol / L HCl solution (200 mL) was added dropwise. The mixture was stirred at room temperature overnight. The reaction solution was concentrated to dryness under reduced pressure, ethyl acetate and water were added, stirred and separated, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined, washed once with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The intermediate compound (5) (14.3 g, yield 94.7%) was obtained by silica gel column chromatography. LCMS: m / z = 229 [M+H] + .

[0061] Example 5: Preparation of (S)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-ol (6)

[0062]

[0063] In a three-necked flask, 5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-one (5) (15 g, 65.7 mmol), anhydrous tetrahydrofuran (600 mL), (R)-5,5-biphenyl-2-methyl-3,4-propanol-1,3,2-oxazolidinone (2.7 g, 9.9 mmol) were added in sequence, stirred and dissolved; nitrogen was replaced three times, and the temperature was lowered to -10 ° C under nitrogen protection, and borane dimethyl sulfide complex (10.0 M in DMSO, 9.8 mL, 98.5 mmol), the internal temperature was kept below -5°C during the addition process; after the addition was complete, the reaction was carried out at -5 to 5°C for 4 hours, and then the reaction was quenched with water, the solution temperature was kept below 5°C, and the mixture was extracted three times with ethyl acetate. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The intermediate compound (6) (11.9 g, yield 78.6%) was purified by silica gel column chromatography, LCMS: m / z = 231 [M+H] + .

[0064] Example 6: Preparation of (R)-2-(5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)isoindole-1,3-dione (7)

[0065]

[0066] Method 1: To a reaction flask, add (S)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-ol (6) (10 g, 43.4 mmol), phthalimide (7.7 g, 52.1 mmol), triphenylphosphine (13.7 g, 52.1 mmol), and tetrahydrofuran (400 ml) in sequence, stir, and dissolve. Cool to 0-5°C, and add diisopropyl azodicarboxylate (10.5 g, 52.1 mmol) dropwise. After the addition is complete, allow to warm to room temperature and stir overnight. Water was added to quench the reaction, and the liquid was separated. The aqueous phase was extracted three times with ethyl acetate, and the organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness under reduced pressure and purified by silica gel column chromatography to obtain intermediate compound (7) (11.3 g, yield 72.4%), LCMS: m / z = 360 [M+H] + .

[0067] Method 2: In a reaction flask, (S)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-ol (6) (0.5 g, 2.17 mmol), phthalimide (0.38 g, 2.61 mmol), triphenylphosphine (0.68 g, 2.61 mmol) and dichloromethane (50 ml) were added in sequence and stirred to dissolve. The temperature was lowered to 0-5°C and diisopropyl azodicarboxylate (0.53 g, 2.61 mmol) was added dropwise. After the addition was complete, the temperature was naturally raised to room temperature and stirred overnight. After the reaction was completed, water was added to quench the reaction. The liquids were separated and the aqueous phase was extracted with dichloromethane. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure. The filtrate was purified by silica gel column chromatography to obtain the intermediate compound (7) (0.6 g, yield 76.9%).

[0068] Method 3: In a reaction flask, (S)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-ol (6) (0.5 g, 2.17 mmol), phthalimide (0.38 g, 2.61 mmol), triphenylphosphine (0.68 g, 2.61 mmol) and tetrahydrofuran (50 ml) were added in sequence and stirred to dissolve. The temperature was lowered to 0-5°C and diisopropyl azodicarboxylate (0.53 g, 2.61 mmol) was added dropwise. After the addition was complete, the temperature was naturally raised to room temperature and stirred overnight. After the reaction was completed, water was added to quench the reaction. The layers were separated and the aqueous phase was extracted with ethyl acetate. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure. The filtrate was purified by silica gel column chromatography to obtain the intermediate compound (7) (0.55 g, 70.5%).

[0069] Method 4: In a reaction flask, (S)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-ol (6) (0.3 g, 1.30 mmol), phthalimide (0.23 g, 1.56 mmol), triphenylphosphine (0.41 g, 1.56 mmol) and tetrahydrofuran (30 ml) were added in sequence and stirred to dissolve. The temperature was lowered to 0-5°C, di-tert-butyl azodicarboxylate (0.36 g, 1.56 mmol) was added, the temperature was naturally raised to room temperature, and the mixture was stirred overnight. After the reaction was completed, water was added to quench the reaction, the layers were separated, the aqueous phase was extracted with ethyl acetate, the organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure. The filtrate was purified by silica gel column chromatography to obtain the intermediate compound (7) (0.3 g, yield 64.1%).

[0070] Example 7: Preparation of (R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-amine (8)

[0071]

[0072] In a reaction flask, methanol (150 mL), (R)-2-(5-bromo-2,3-dihydro-1H-inden-1-yl)isoindole-1,3-dione (7) (9.5 g, 26.4 mmol), and 80% hydrazine hydrate (15.9 g, 264.3 mmol) were added in sequence. The mixture was stirred and heated to 50°C. The reaction was kept warm overnight. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The intermediate compound (8) (5.3 g, yield 87.4%) was purified by silica gel column chromatography. LCMS: m / z = 230 [M+H] + .

[0073] Example 8: Preparation of Aficamten (10)

[0074]

[0075] Method 1: In a reaction flask, dichloromethane (100 mL) and 1-methyl-1H-pyrazole-4-carboxylic acid (9) (2.5 g, 19.6 mmol) were added in sequence and stirred to dissolve; the temperature was lowered to 0-5°C, and N,N-diisopropylethylamine (DIPEA) (6.34 g, 19.6 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (5.6 g, 29.4 mmol), and 1-hydroxybenzotriazole (HOBT) (0.5 g, 3.9 mmol) were added in sequence, and the mixture was stirred for 30 min; the mixture was added dropwise at 0-5°C. A solution of (R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-amine (8) (4.5 g, 19.6 mmol) in dichloromethane (100 mL) was added dropwise, and the mixture was stirred overnight. A 10% aqueous ammonium chloride solution was added to the reaction solution to quench the reaction. The layers were separated and the organic phase was retained. The organic phase was washed once with saturated sodium bicarbonate and saturated brine, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography to obtain the final product, Aficamten (5.4 g, yield 81.5%), LCMS: m / z = 338 [M+H] +. 1H-NMR: (DMSO-d6, 400MHz): δ8.41-8.43ppm (m, 1H), 8.15ppm (m, 1H), 7.77-7.90ppm (m, 3H), 7.32-7.34ppm (m, 1H), 5.51-5.5 3ppm (m, 1H), 3.85ppm (s, 3H), 2.83-3.12ppm (m, 4H), 2.40-2.44ppm (m, 1H), 1.97-2.01ppm (m, 1H), 1.34ppm (t, J=10.0Hz, 3H).

[0076] Method 2: 1-methyl-1H-pyrazole-4-carboxylic acid (9) (0.44 g, 3.49 mmol) and thionyl chloride (10 mL) were added to a reaction flask, the temperature was raised to reflux, and the reaction was kept warm for 3 hours; the temperature was lowered to room temperature, the mixture was concentrated to dryness under reduced pressure, anhydrous dichloromethane (10 mL) was added, and the mixture was stirred and dispersed; under an ice-water bath, the above-mentioned turbid dichloromethane solution was added in batches with (R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-indene-1-amine (8 )(0.2 g, 0.87 mmol), triethylamine (0.71 g, 6.98 mmol) in dichloromethane (20 mL), the transfer was completed, the temperature was naturally raised to room temperature, and the reaction was allowed to react overnight; an appropriate amount of water was added to the reaction solution to quench the reaction, the liquids were separated, and the dichloromethane extraction was retained, and the organic phase was retained; the organic phase was washed once with saturated sodium bicarbonate and saturated brine in sequence, the organic phase was concentrated to dryness under reduced pressure, and purified by silica gel column chromatography to obtain the final product Aficamten (0.21 g, yield 71.4%).

[0077] The above describes the specific embodiments of the present invention. It should be understood that the present invention is not limited to the above specific embodiments, and those skilled in the art may make various variations or modifications within the scope of the claims, which do not affect the essence of the present invention.

Claims

1. A method for preparing Aficamten, characterized in that: The method comprises the following steps: S1: Compound 1 reacts with ethylene glycol in the presence of an acidic reagent to obtain intermediate compound 2; S2: Intermediate compound 2 and hydroxylamine hydrochloride are reacted with an alkaline reagent to prepare intermediate compound 3; S3: Intermediate compound 3 undergoes a cyclization reaction with propionic anhydride at a certain reaction temperature to prepare intermediate compound 4; S4: Intermediate compound 4 undergoes hydrolysis reaction in an organic solvent under acidic conditions to prepare intermediate compound 5; S5: Intermediate compound 5 undergoes Noyori asymmetric hydrogenation reaction in the presence of a chiral catalyst to prepare intermediate compound 6; S6: Intermediate compound 6 undergoes Mitsunobu reaction with phthalimide to prepare intermediate compound 7; S7: Intermediate compound 7 undergoes hydrazine hydrolysis reaction under the action of hydrazine hydrate to prepare intermediate compound 8; S8: The intermediate compound 8 undergoes a condensation reaction with 1-methyl-1H-pyrazole-4-carboxylic acid to prepare the target product Aficamten; The reaction route is as follows:

2. The method for preparing Aficamten according to claim 1, wherein In step S1, the acidic reagent is p-toluenesulfonic acid, and the molar ratio of compound 1 to the acidic reagent is 5:1 to 2:

1.

3. The method for preparing Aficamten according to claim 1, wherein The alkaline reagent in step S2 is one of sodium bicarbonate, sodium carbonate, potassium carbonate, and sodium hydroxide, and the molar ratio of the intermediate compound 2 to hydroxylamine hydrochloride is 1:4 to 1:

8.

4. The method for preparing Aficamten according to claim 1, wherein The cyclization reaction temperature in step S3 is 60-80° C., and the molar ratio of the intermediate compound 3 to propionic anhydride is 1:1.1-1:

5.

5. The method for preparing Aficamten according to claim 1, wherein The organic solvent in step S4 is one of dichloromethane, ethyl acetate, and 1,4-dioxane. The reaction temperature is room temperature. The acidic reagent used is dilute hydrochloric acid with a concentration of 1 to 3 mol / L.

6. The method for preparing Aficamten according to claim 1, wherein In step S5, the chiral catalyst is (R)-5,5-biphenyl-2-methyl-3,4-propanol-1,3,2-oxazolidinone, and the molar ratio of the intermediate compound 5 to (R)-5,5-biphenyl-2-methyl-3,4-propanol-1,3,2-oxazolidinone is 5:1 to 10:

1.

7. The method for preparing Aficamten according to claim 1, wherein In step S6, the organic solvent is one of tetrahydrofuran, dichloromethane, and acetonitrile, the coupling reagent is one of diethyl azodicarboxylate, diisopropyl azodicarboxylate, and di-tert-butyl azodicarboxylate, the molar ratio of the intermediate compound 6 to the coupling reagent is 1:1 to 1:5, and the reaction is a room temperature reaction.

8. The method for preparing Aficamten according to claim 1, wherein In step S7, the reaction temperature is 40-60° C., and the molar ratio of the intermediate compound 7 to hydrazine hydrate is 1:8-1:

20.

9. The method for preparing Aficamten according to claim 1, wherein In step S8, the condensing agent is one or more of N,N-diisopropylethylamine DIPEA, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride EDCI, 1-hydroxybenzotriazole HOBT, and thionyl chloride SOCl2, and the molar ratio of the intermediate to the condensing agent is: Intermediate compound 8: DIPEA:EDCI:HOBT=1:1:1.5:0.2; Intermediate compound 8: SOCl2=1:(2-3).

Images