A method for the synthesis of pimobendan

Abstract

The application discloses a synthesis method of pimobendan, which comprises the following steps: a Friedel-Crafts acylation reaction: compound I and compound A are subjected to a Friedel-Crafts acylation reaction in aprotic solvent under the action of a Lewis acid to generate compound II; a substitution and hydrolysis reaction: under alkaline conditions, compound II and dimethyl malonate or diethyl malonate are subjected to a substitution reaction in an ether solvent, and the generated compound is subjected to a hydrolysis reaction in an alkaline aqueous solution to generate compound III; a decarboxylation and ring-closing reaction: compound III is heated under the condition of hydrazine hydrate and acid to generate compound IV; a substitution reaction: compound IV and an amine are subjected to a substitution reaction in a polar solvent to generate compound V; a reduction reaction: compound V is subjected to a reaction in an acidic aqueous solution of a protic solvent under the condition of palladium-carbon and hydrogen to generate compound VI; and a ring-closing reaction, so that the pimobendan is obtained. The method has high safety, short line steps and simple operation.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical organic chemical synthesis technology, and in particular to a method for synthesizing pimoxendan. Background Technology

[0002] Pimobendan (UD-CG115BS, Acardi, CAS: 74150-27-9) is a vasodilator cardiotonic drug developed by Boehringer Ingelheim, Germany, and first marketed in Japan in 1994. It belongs to the phosphodiesterase inhibitor class and is primarily used clinically for the treatment of heart failure. Its mechanism of action differs from traditional cardiotonic drugs; its positive inotropic effect is mainly attributed to enhancing the effect of myocardial contractile proteins on calcium. 2+ It exhibits high sensitivity and inhibitory activity against phosphodiesterase III (PDEIII), making it the first marketed calcium sensitizer. The chemical name of this product is: 4,5-dihydro-6-[2-(4-methoxyphenyl)-1H-benzimidazol-5-yl]-5-methyl-3(2H)-pyridazinone, with the following chemical structural formula:

[0003]

[0004] Since pimoxendan was launched in Japan, its preparation method has become a focus of attention. Currently, the starting materials for pimoxendan preparation on the market include chlorobenzene, 4-chlorobenzaldehyde, or acetanilide. These routes all require nitration reactions, which are highly dangerous, easily generating large amounts of strong acid wastewater, and the routes are relatively long. Some reactions require the use of highly toxic potassium cyanide or bromine, while others require column chromatography purification. These are all unfavorable factors for pimoxendan production.

[0005] The original patent US4361563A reported the preparation of pimoxendan from chlorobenzene in eleven steps. These steps included a highly dangerous nitration reaction, the use of highly toxic bromine, and a relatively long process (Scheme 1).

[0006] Scheme 1:

[0007]

[0008] The literature “R Jonas, M Klockow, I Lues. Eur. J. Med. Chem. 1993, 28, 129” reports a seven-step process to obtain pimoxendan from 4-chlorobenzaldehyde as a starting material, which uses the highly toxic potassium cyanide and involves a nitration reaction. This route is too dangerous for industrial production and would generate a large amount of acidic wastewater (Scheme 2).

[0009] Scheme 2:

[0010]

[0011] The literature “Pu Riyang et al., Chinese Journal of Medicinal Chemistry, 1994, 4(1), 41” reports the synthesis of pyridazinone intermediates from acetylaniline as a starting material in six steps. This route also uses the highly toxic potassium cyanide and involves a nitration reaction (Scheme 3).

[0012] Scheme 3:

[0013]

[0014] The literature “Wang Sisi, Shen Jiacong. Chinese Journal of Medicinal Chemistry, 1997, 7(3), 185” reported the preparation of pimoxand from acetanilide in seven steps. This route uses a relatively dangerous nitration reaction and a relatively toxic bromine, and the steps are relatively long, and each step requires column purification (Scheme 4).

[0015] Scheme 4:

[0016]

[0017] Patent CN106518850A reports a six-step process to obtain pimoxendan from acetanilide as a starting material. This route not only uses a nitration reaction, but also the starting material 2-methyl-3-methoxycarbonylpropionyl chloride is not a chemical product and is difficult to obtain in large quantities on the market, which is not conducive to scale-up production (Scheme 5).

[0018] Scheme 5:

[0019]

[0020] Patents CN107522663A and CN111518081A propose a seven-step process to obtain pimoxendan from acetanilide as a starting material. This route not only involves nitration but also has a relatively long procedure (Scheme 6).

[0021] Scheme 6:

[0022]

[0023] In summary, the publicly reported synthetic routes for pimoxendan all utilize industrially limited but highly toxic starting materials such as bromine, potassium cyanide, or other difficult-to-obtain raw materials. Furthermore, all routes involve nitration reactions that are highly hazardous and generate significant amounts of acidic wastewater, making them unsuitable for large-scale industrial production. Therefore, developing a synthetic route for pimoxendan suitable for industrial-scale production is crucial for the industrialization of this drug. Summary of the Invention

[0024] The purpose of this invention is to provide a method for synthesizing pimoxendan, thereby solving one or more of the problems in the prior art.

[0025] The present invention provides a method for synthesizing pimoxane, comprising the following steps:

[0026] Step 1, Friedel-Crafts acylation reaction: Compound I and compound A undergo a Friedel-Crafts acylation reaction in an aprotic solvent under the action of a Lewis acid to generate compound II;

[0027] Step 2, Substitution and Hydrolysis Reaction: Using ether as a solvent, under alkaline conditions, compound II undergoes a substitution reaction with dimethyl malonate or diethyl malonate. The resulting compound undergoes a hydrolysis reaction in an alkaline aqueous solution to generate compound III.

[0028] Step 3, decarboxylation and ring-closure reaction: Compound III is heated under the conditions of hydrazine hydrate and acid to generate compound IV;

[0029] Step 4, Substitution Reaction: Compound IV undergoes a substitution reaction with an amine in a polar solvent to produce compound V;

[0030] Step 5, Reduction reaction: Compound V reacts in an acidic aqueous solution of a protic solvent under the conditions of palladium on carbon and hydrogen to produce compound VI;

[0031] Step 6: Ring-closing reaction, to obtain the pimoxendan;

[0032] The reaction equation is as follows:

[0033]

[0034] Wherein: R is F, Cl, Br or a lower alkoxy group, and the lower alkoxy group is an alkoxy group with ≤3 carbon atoms; R1 is Cl or Br; R2 is methyl or ethyl; R3 is H, benzyl or p-methoxybenzyl.

[0035] In some embodiments, the Lewis acid in step one includes, but is not limited to, the following compounds: aluminum trichloride, ferric trichloride, or zinc chloride; the aprotic solvent includes, but is not limited to, the following solvents: dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, or carbon disulfide; when R1 is Cl, the reaction temperature is 30–80°C; when R1 is Br, the reaction temperature is -20–30°C; the molar ratio of compound I: compound A: Lewis acid is 1:1.05–1.3:1.5–3.

[0036] In some embodiments, the ether in step two includes, but is not limited to, the following compounds: diethyl ether, tetrahydrofuran, methyl tert-butyl ether, dioxane, ethylene glycol dimethyl ether, or ethylene glycol diethyl ether; the base in the alkaline conditions includes, but is not limited to, sodium hydroxide, sodium methoxide, or sodium ethoxide; the base in the alkaline aqueous solution includes, but is not limited to, lithium hydroxide, sodium hydroxide, or potassium hydroxide; the reaction temperature is -20 to 30°C; the molar ratio of compound II: dimethyl malonate or ethyl malonate: base: alkaline solution is 1:1.2 to 2.5:1.5 to 3:3 to 5.

[0037] In some embodiments, the acid in step three includes, but is not limited to, formic acid, acetic acid, and propionic acid; the reaction temperature is 60–115°C; and the molar ratio of compound III to hydrazine hydrate is 1:2–5.

[0038] In some embodiments, the solvent used in step four is N,N-dimethylformamide, N,N-dimethylacetamide, or n-butanol.

[0039] In some implementations, the reaction temperature in step four is 90–110°C.

[0040] In some embodiments, in step four, when R3 = H, NH3 is in excess and the pressure inside the reactor is 0.2 to 10 Bar; when R3 is benzyl or methoxybenzyl, the molar ratio of compound IV to NH2R3 is 1:3 to 8.

[0041] In some embodiments, the solvent used in step five is methanol, ethanol, propanol or isopropanol, preferably methanol; the acid in the acidic aqueous solution is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, formic acid or acetic acid, preferably hydrochloric acid.

[0042] In some implementations, the reaction temperature in step five is 30–60°C; and the hydrogen pressure is controlled at 0.2–0.9 Bar.

[0043] In some embodiments, the weight ratio of compound V to palladium on carbon (dry or wet palladium on carbon containing 5 wt% palladium, or dry or wet palladium on carbon containing 10 wt% palladium) in step five is 1:0.01 to 0.1.

[0044] Step Six: Compound VI undergoes a cyclization reaction with p-methoxybenzaldehyde. For specific synthetic methods, refer to patent WO2011124638A.

[0045] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0046] (1) The nitration reaction step, which is highly dangerous and generates a large amount of waste acid water, has been eliminated;

[0047] (2) This route has a short procedure, and pimoxand can be obtained in six steps;

[0048] (3) All raw and auxiliary materials used in this route are industrially available and readily purchased products;

[0049] (4) This route is simple to operate and does not require column chromatography purification. Detailed Implementation

[0050] The present invention will be further described in detail below through embodiments.

[0051] Example 1

[0052] Preparation of compound II:

[0053] When R1 = Cl:

[0054] Dichloromethane (500 mL), o-chloronitrobenzene (0.32 mol, 50 g), and 2-chloropropionyl chloride (0.33 mol, 42.31 g) were added sequentially to a reaction flask. Ferric chloride (0.48 mol, 77.86 g) was added at room temperature. The mixture was heated to 30–40 °C and reacted for 5 h until the reaction was complete. The mixture was then cooled to room temperature and poured into 500 mL of ice water under stirring. The mixture was separated, and the organic phase was washed sequentially with water (150 mL), ice-saturated sodium bicarbonate solution (150 mL), and aqueous solution (150 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was crystallized from a mixed solution of ethyl acetate and petroleum ether to obtain 62.98 g of 2-chloro-1-(4-chloro-3-nitrophenyl)-prop-1-one.

[0055] Example 2

[0056] Preparation of compound II:

[0057] When R1 = Cl:

[0058] 1,2-Dichloroethane (500 mL), o-fluoronitrobenzene (0.35 mol, 50 g), and 2-chloropropionyl chloride (0.41 mol, 51.74 g) were added sequentially to a reaction flask. Zinc chloride (1.06 mol, 144.48 g) was added at room temperature. The mixture was heated to 70–80 °C and reacted for 2 h until the reaction was complete. The mixture was then cooled to room temperature and poured into 500 mL of ice water under stirring. The mixture was separated, and the organic phase was washed sequentially with water (150 mL), ice-saturated sodium bicarbonate solution (150 mL), and aqueous solution (150 mL). The mixture was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was crystallized from a mixed solution of ethyl acetate and petroleum ether to obtain 66.47 g of 2-chloro-1-(4-fluoro-3-nitrophenyl)-prop-1-one.

[0059] Example 3

[0060] Preparation of compound II:

[0061] When R1 = Cl:

[0062] Carbon disulfide (500 mL), 4-ethoxynitrobenzene (0.3 mol, 50 g), and 2-chloropropionyl chloride (0.39 mol, 49.37 g) were added sequentially to a reaction flask. Aluminum trichloride (0.6 mol, 80.00 g) was added at room temperature, and the mixture was heated to reflux and reacted for 3 hours until the reaction was complete. The mixture was then cooled to room temperature and poured into 500 mL of ice water under stirring. The mixture was separated, and the organic phase was washed sequentially with water (150 mL), ice-saturated sodium bicarbonate solution (150 mL), and aqueous solution (150 mL). The mixture was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was crystallized from a mixed solution of ethyl acetate and petroleum ether to obtain 46.24 g of 2-chloro-1-(4-ethoxy-3-nitrophenyl)-prop-1-one.

[0063] Example 4

[0064] Preparation of compound II:

[0065] When R1 = Br:

[0066] Carbon tetrachloride (500 mL), o-bromonitrobenzene (0.25 mol, 50 g), and 2-bromopropionyl bromide (0.32 mol, 69.46 g) were added sequentially to a reaction flask. The mixture was cooled to -20 °C, and aluminum trichloride (0.74 mol, 99.01 g) was added in portions. After the addition was complete, the mixture was slowly brought back to room temperature and allowed to react for 1 hour until the reaction was complete. The mixture was then poured into 500 mL of ice water under stirring. The mixture was separated, and the organic phase was washed sequentially with water (150 mL), ice-saturated sodium bicarbonate solution (150 mL), and aqueous solution (150 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was crystallized from a mixture of ethyl acetate and petroleum ether to give 70.89 g of 2-bromo-1-(4-bromo-3-nitrophenyl)-prop-1-one.

[0067] Example 5

[0068] Preparation of compound II:

[0069] When R1 = Br:

[0070] Chloroform (500 mL), 4-isopropoxynitrobenzene (0.28 mol, 50 g), and 2-bromopropionyl bromide (0.33 mol, 71.48 g) were added sequentially to a reaction flask and cooled to -10 °C. Zinc chloride (0.41 mol, 56.42 g) was added in portions, and the mixture was allowed to slowly return to room temperature. The reaction was allowed to proceed for 3 hours until complete. The mixture was poured into 500 mL of ice water under stirring. The mixture was separated, and the organic phase was washed sequentially with water (150 mL), ice-saturated sodium bicarbonate solution (150 mL), and aqueous solution (150 mL). The phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was crystallized from a mixture of ethyl acetate and petroleum ether to obtain 52.35 g of 2-bromo-1-(4-isopropoxy-3-nitrophenyl)-prop-1-one.

[0071] Example 6

[0072] Preparation of compound II:

[0073] When R1 = Br:

[0074] Dichloromethane (500 mL), 4-methoxynitrobenzene (0.33 mol, 50 g), and 2-bromopropionyl bromide (0.36 mol, 77.53 g) were added sequentially to a reaction flask and cooled to -15 °C. Ferric chloride (0.65 mol, 105.92 g) was added in portions, and the mixture was allowed to slowly return to room temperature. The reaction was allowed to proceed for 1 hour until complete. The mixture was poured into 500 mL of ice water under stirring. The mixture was separated, and the organic phase was washed sequentially with water (150 mL), ice-saturated sodium bicarbonate solution (150 mL), and aqueous solution (150 mL). The phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was crystallized from a mixture of ethyl acetate and petroleum ether to give 47.03 g of 2-bromo-1-(4-methoxy-3-nitrophenyl)-prop-1-one.

[0075] Example 7

[0076] Preparation of compound III:

[0077] When R2 = Me:

[0078] Tetrahydrofuran (320 mL) and sodium hydride (0.24 mol, 8.47 g) were added sequentially to a reaction flask, stirred until homogeneous, and cooled to -20 °C. Dimethyl malonate (0.19 mol, 25.56 g) was added dropwise. After the addition was complete, the reaction was carried out at a temperature not exceeding 10 °C for 30 minutes. Then, 2-chloro-1-(4-chloro-3-nitrophenyl)-prop-1-one (0.16 mol, 40 g) was added, and the reaction was carried out at a temperature not exceeding 30 °C for 5–6 hours until the reaction was complete. Finally, 250 g of sodium hydroxide (0.81 mol, 32.25 g) aqueous solution was added dropwise, and the reaction was carried out at a temperature not exceeding 30 °C until the reaction was complete as detected by TLC. Cool to -10℃, add ice water (100mL) and methyl tert-butyl ether (300mL), stir, separate the liquid and water, adjust the pH of the aqueous phase to ≈1 with concentrated hydrochloric acid in an ice bath, extract with ethyl acetate (300mL×3), wash the organic phase with saturated saline solution (300mL), dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure to obtain 50.39g of (2-carboxy-3-(3-nitro-4-chlorobenzoyl)-butyric acid.

[0079] Example 8

[0080] Preparation of compound III:

[0081] When R2 = Me:

[0082] In a reaction flask, 320 mL of methyl tert-butyl ether and 0.44 mol (23.86 g) were added sequentially and stirred until homogeneous. The mixture was then cooled to -20 °C, and dimethyl malonate (0.29 mol (38.9 g) was added dropwise. After the addition was complete, the mixture was reacted at a temperature not exceeding 10 °C for 30 minutes. Then, 0.15 mol (40 g) of 2-chloro-1-(4-isopropoxy-3-nitrophenyl)-prop-1-one was added, and the mixture was reacted at a temperature not exceeding 30 °C for 5–6 hours until the reaction was complete. Finally, 250 g of an aqueous solution of 0.44 mol (24.78 g) of potassium hydroxide was added dropwise, and the mixture was reacted at a temperature not exceeding 30 °C until the reaction was complete as detected by TLC. Cool to -10℃, add ice water (100mL) and stir. Separate the liquid and aqueous phases. Adjust the pH of the aqueous phase to ≈1 with concentrated hydrochloric acid in an ice bath. Extract with ethyl acetate (300mL×3). Wash the organic phase with saturated saline solution (300mL), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 48.45g of (2-carboxy-3-(3-nitro-4-isopropoxybenzoyl)-butyric acid.

[0083] Example 9

[0084] Preparation of compound III:

[0085] When R2 = Me:

[0086] Ethylene glycol dimethyl ether (320 mL) and sodium ethoxide (0.29 mol, 23.86 g) were added sequentially to a reaction flask, stirred until homogeneous, and cooled to -20 °C. Dimethyl malonate (0.29 mol, 39.21 g) was added dropwise. After the addition was complete, the reaction was carried out at a temperature not exceeding 10 °C for 30 minutes. Then, 2-bromo-1-(4-bromo-3-nitrophenyl)-prop-1-one (0.12 mol, 40 g) was added, and the reaction was carried out at a temperature not exceeding 30 °C for 5–6 hours until the reaction was complete. Finally, 250 g of lithium hydroxide (0.47 mol, 11.37 g) aqueous solution was added dropwise, and the reaction was carried out at a temperature not exceeding 30 °C until the reaction was complete as detected by TLC. Cool to -10℃, add ice water (100mL) and methyl tert-butyl ether (300mL), stir, separate the liquid and water, adjust the pH of the aqueous phase to ≈1 with concentrated hydrochloric acid in an ice bath, extract with ethyl acetate (300mL×3), wash the organic phase with saturated saline solution (300mL), dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure to obtain 42.32g of (2-carboxy-3-(3-nitro-4-bromobenzoyl)-butyric acid.

[0087] Example 10

[0088] Preparation of compound III:

[0089] When R2 = Et:

[0090] Add diethyl ether (320 mL) and sodium methoxide (0.36 mol, 19.57 g) sequentially to a reaction flask, stir until homogeneous, cool to -20 °C, add diethyl malonate (0.17 mol, 27.85 g) dropwise, and react at a temperature not exceeding 10 °C for 30 minutes. Then add 2-bromo-1-(4-fluoro-3-nitrophenyl)-prop-1-one (0.14 mol, 40 g), and react at a temperature not exceeding 30 °C for 5–6 hours until the reaction is complete. Add 250 g of lithium hydroxide (0.43 mol, 10.41 g) aqueous solution dropwise, and react at a temperature not exceeding 30 °C until the reaction is complete as detected by TLC. Cool to -10℃, add ice water (100mL) and stir. Separate the liquid and aqueous phases. Adjust the pH of the aqueous phase to ≈1 with concentrated hydrochloric acid in an ice bath. Extract with ethyl acetate (300mL×3). Wash the organic phase with saturated saline solution (300mL), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 42.92g of (2-carboxy-3-(3-nitro-4-fluorobenzoyl)-butyric acid.

[0091] Example 11

[0092] Preparation of compound III:

[0093] When R2 = Et:

[0094] Tetrahydrofuran (320 mL) and sodium ethoxide (0.28 mol, 18.9 g) were added sequentially to a reaction flask, stirred until homogeneous, and cooled to -20 °C. Diethyl malonate (0.21 mol, 34.22 g) was added dropwise. After the addition was complete, the reaction was carried out at a temperature not exceeding 10 °C for 30 minutes. Then, 2-bromo-1-(4-methoxy-3-nitrophenyl)-prop-1-one (0.14 mol, 40 g) was added, and the reaction was carried out at a temperature not exceeding 30 °C for 5–6 hours until the reaction was complete. Finally, 250 g of sodium hydroxide (0.47 mol, 18.99 g) aqueous solution was added dropwise, and the reaction was carried out at a temperature not exceeding 30 °C until the reaction was complete as detected by TLC. Cool to -10℃, add ice water (100mL) and methyl tert-butyl ether (300mL), stir, separate the liquid and water, adjust the pH of the aqueous phase to ≈1 with concentrated hydrochloric acid in an ice bath, extract with ethyl acetate (300mL×3), wash the organic phase with saturated saline solution (300mL), dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure to obtain 41.49g of (2-carboxy-3-(3-nitro-4-methoxybenzoyl)-butyric acid.

[0095] Example 12

[0096] Preparation of compound III:

[0097] When R2 = Et:

[0098] Ethylene glycol dimethyl ether (320 mL) and sodium hydride (0.47 mol, 18.63 g) were added sequentially to a reaction flask, stirred until homogeneous, and cooled to -20 °C. Diethyl malonate (0.39 mol, 62.16 g) was added dropwise. After the addition was complete, the reaction was carried out at a temperature not exceeding 10 °C for 30 minutes. Then, 2-chloro-1-(4-ethoxy-3-nitrophenyl)-prop-1-one (0.16 mol, 40 g) was added, and the reaction was carried out at a temperature not exceeding 30 °C for 5–6 hours until the reaction was complete. Finally, 250 g of potassium hydroxide (0.78 mol, 56.11 g) aqueous solution was added dropwise, and the reaction was carried out at a temperature not exceeding 30 °C until the reaction was complete as detected by TLC. Cool to -10℃, add ice water (100mL) and methyl tert-butyl ether (300mL), stir, separate the liquid and water, adjust the pH of the aqueous phase to ≈1 with concentrated hydrochloric acid in an ice bath, extract with ethyl acetate (300mL×3), wash the organic phase with saturated saline solution (300mL), dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure to obtain 48.48g of (2-carboxy-3-(3-nitro-4-ethoxybenzoyl)-butyric acid.

[0099] Example 13

[0100] Preparation of compound IV:

[0101] Formic acid (120 mL), (0.13 mol, 40 g) of (2-carboxy-3-(3-nitro-4-fluorobenzoyl)-butyric acid, and 0.27 mol, 16.73 g of 80% hydrazine hydrate were added sequentially to a reaction flask. The mixture was heated to 60–70 °C and reacted for 24 h. After cooling to room temperature, 200 mL of ice water was slowly poured in, and the mixture was stirred in an ice bath for 1 h. The mixture was then filtered and dried to obtain 28.55 g of 6-(3-nitro-4-fluorophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone. MS (ESI): 252.1 [M+H] + .

[0102] Example 14

[0103] Preparation of compound IV:

[0104] Formic acid (160 mL), (0.13 mol, 40 g) of 2-carboxy-3-(3-nitro-4-chlorobenzoyl)-butyric acid, and 0.51 mol, 31.72 g of 80% hydrazine hydrate were added sequentially to a reaction flask. The mixture was heated to 80–90 °C and reacted for 16 h. After cooling to room temperature, 240 mL of ice water was slowly poured in, and the mixture was stirred in an ice bath for 1 h. The mixture was then filtered and dried to obtain 28.83 g of 6-(3-nitro-4-chlorophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone. MS (ESI): 268.6 [M+H] + .

[0105] Example 15

[0106] Preparation of compound IV:

[0107] Acetic acid (160 mL), (0.13 mol, 40 g) of 2-carboxy-3-(3-nitro-4-methoxybenzoyl)-butyric acid, and 80% hydrazine hydrate (0.39 mol, 24.13 g) were added sequentially to a reaction flask. The mixture was heated to 90–100 °C and reacted for 12 h. After cooling to room temperature, 240 mL of ice water was slowly poured in, and the mixture was stirred in an ice bath for 1 h. The mixture was then filtered and dried to obtain 27.07 g of 6-(3-nitro-4-methoxyphenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone. MS (ESI): 263.9 [M+H] + .

[0108] Example 16

[0109] Preparation of compound IV:

[0110] Propionic acid (120 mL), (0.12 mol, 40 g) of (2-carboxy-3-(3-nitro-4-ethoxybenzoyl)-butyric acid, and 0.61 mol, 38.48 g of 80% hydrazine hydrate were added sequentially to a reaction flask. The mixture was heated to 100–115 °C and reacted for 8 h. After cooling to room temperature, 200 mL of ice water was slowly poured in, and the mixture was stirred in an ice bath for 1 h. The mixture was then filtered and dried to obtain 27.28 g of 6-(3-nitro-4-ethoxyphenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone. MS (ESI): 277.9 [M+H] + .

[0111] The preparation method for 6-(3-nitro-4-bromophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone is the same as above. MS (ESI): 313.1 [M+H] + .

[0112] The preparation method for 6-(3-nitro-4-propoxyphenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone is the same as above. MS (ESI): 291.9 [M+H] + .

[0113] The preparation method for 6-(3-nitro-4-isopropoxyphenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone is the same as above. MS (ESI): 291.9 [M+H] + .

[0114] Example 17

[0115] Preparation of compound V:

[0116] When R3 = H:

[0117] In a reaction vessel, N,N-dimethylacetamide (200 mL) and 6-(3-nitro-4-fluorophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (0.08 mol, 20 g) were added sequentially. Under stirring, a vacuum was drawn, ammonia gas was introduced, and the mixture was heated to 90–100 °C at a pressure of 0.2–0.4 bar for 24 h. The reaction was confirmed to be complete by TLC. The mixture was then cooled to room temperature, 600 mL of water was added, and the mixture was stirred, filtered, washed with water, and dried to obtain 17.79 g of 6-(3-nitro-4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone.

[0118] Example 18

[0119] Preparation of compound V:

[0120] When R3 = H:

[0121] In a reaction vessel, N,N-dimethylformamide (200 mL) and 6-(3-nitro-4-chlorophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (0.07 mol, 20 g) were added sequentially. Under stirring, a vacuum was drawn, ammonia gas was introduced, and the mixture was heated to 100–110 °C at a pressure of 0.8–1 bar. The reaction was carried out for 24 h, and TLC was used to confirm that the reaction was complete. The mixture was then cooled to room temperature, 600 mL of water was added, and the mixture was stirred, filtered, washed with water, and dried to obtain 17.06 g of 6-(3-nitro-4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone.

[0122] Example 19

[0123] Preparation of compound V:

[0124] When R3 = H:

[0125] In a reaction vessel, N,N-dimethylformamide (200 mL) and 6-(3-nitro-4-methoxyphenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (0.08 mol, 20 g) were added sequentially. Under stirring, a vacuum was drawn, ammonia gas was introduced, and the mixture was heated to 100–110 °C at a pressure of 1–2 bar. The reaction was carried out for 12 h, and TLC was used to confirm that the reaction was complete. The mixture was then cooled to room temperature, 600 mL of water was added, and the mixture was stirred, filtered, washed with water, and dried to obtain 16.97 g of 6-(3-nitro-4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone.

[0126] Example 20

[0127] Preparation of compound V:

[0128] When R3 = H:

[0129] In a reaction vessel, n-butanol (200 mL) and 6-(3-nitro-4-ethoxyphenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (0.07 mol, 20 g) were added sequentially. Under stirring, a vacuum was drawn, ammonia gas was introduced, and the mixture was heated to 90–100 °C at a pressure of 8–10 bar. The reaction was carried out for 10 h, and TLC was used to confirm that the reaction was complete. The mixture was then cooled to room temperature, 600 mL of water was added, and the mixture was stirred, filtered, washed with water, and dried to obtain 16.11 g of 6-(3-nitro-4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone.

[0130] Example 21

[0131] Preparation of compound V:

[0132] When R3 = benzyl or p-methoxybenzyl:

[0133] In a reaction flask, N,N-dimethylacetamide (60 mL), 6-(3-nitro-4-chlorophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (0.07 mol, 20 g), and p-methoxybenzylamine (0.22 mol, 30.75 g) were added sequentially. The mixture was heated to 90–100 °C and reacted for 12 h. The reaction was confirmed to be complete by TLC. The mixture was then cooled to room temperature, 180 mL of water was added, and the mixture was filtered, washed with water, and dried to obtain 26.15 g of 6-(3-nitro-4-p-methoxybenzylaminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone.

[0134] Example 22

[0135] Preparation of compound V:

[0136] When R3 = benzyl or p-methoxybenzyl:

[0137] In a reaction flask, N,N-dimethylformamide (80 mL), 6-(3-nitro-4-bromophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (0.06 mol, 20 g), and benzylamine (0.32 mol, 34.33 g) were added sequentially. The mixture was heated to 100–110 °C and reacted for 12 h. The reaction was confirmed to be complete by TLC. The mixture was then cooled to room temperature, 240 mL of water was added, and the mixture was filtered, washed with water, and dried to obtain 20.81 g of 6-(3-nitro-4-benzylaminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone.

[0138] Example 23

[0139] Preparation of compound V:

[0140] When R3 = benzyl or p-methoxybenzyl:

[0141] In a reaction flask, N,N-dimethylformamide (100 mL), 6-(3-nitro-4-methoxyphenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (0.08 mol, 20 g), and benzylamine (0.53 mol, 56.98 g) were added sequentially. The mixture was heated to 90–100 °C and reacted for 10 h. The reaction was confirmed to be complete by TLC. The mixture was then cooled to room temperature, 400 mL of water was added, and the mixture was filtered, washed with water, and dried to obtain 24.42 g of 6-(3-nitro-4-benzylaminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone.

[0142] Example 24

[0143] Preparation of compound V:

[0144] When R3 = benzyl or p-methoxybenzyl:

[0145] In a reaction flask, n-butanol (100 mL), 6-(3-nitro-4-isopropoxyphenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (0.07 mol, 20 g), and p-methoxybenzylamine (0.55 mol, 75.35 g) were added sequentially. The mixture was heated to 100℃~110℃ and reacted for 10 h. The reaction was confirmed to be complete by TLC. The mixture was then cooled to room temperature, 400 mL of water was added, and the mixture was filtered, washed with water, and dried to obtain 24.28 g of 6-(3-nitro-4-p-methoxybenzylaminephenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone.

[0146] Example 25

[0147] Preparation of compound VI:

[0148] When R3 = H:

[0149] In a reaction flask, methanol (200 mL), 6-(3-nitro-4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (0.08 mol, 20 g), hydrobromic acid aqueous solution (1 N, 60 mL), and 10% palladium on carbon (0.2 g) were added sequentially. The mixture was evacuated to purge nitrogen, followed by evacuation to purge hydrogen. The mixture was heated to 50–60 °C at a pressure of 0.7–0.9 bar. The reaction was monitored by TLC until complete. The mixture was cooled to room temperature, filtered, and the pH of the filtrate was adjusted to approximately 7 with sodium hydroxide aqueous solution. The methanol was concentrated under reduced pressure, cooled to 0–10 °C, stirred for 1 h, filtered, and the filter cake was washed with water and dried to obtain 15.83 g of 6-(3,4-diaminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone.

[0150] Example 26

[0151] Preparation of compound VI:

[0152] When R3 = H:

[0153] In a reaction flask, methanol (140 mL), 6-(3-nitro-4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (0.08 mol, 20 g), hydrochloric acid aqueous solution (1 N, 60 mL), and 5% palladium on carbon (1 g) were added sequentially. The mixture was evacuated to purge nitrogen, followed by evacuation to purge hydrogen. The mixture was heated to 40–50 °C at a pressure of 0.5–0.7 bar. The reaction was monitored by TLC until complete. The mixture was cooled to room temperature, filtered, and the pH of the filtrate was adjusted to approximately 7 with sodium hydroxide aqueous solution. The methanol was concentrated under reduced pressure, cooled to 0–10 °C, stirred for 1 h, filtered, and the filter cake was washed with water and dried to obtain 15.65 g of 6-(3,4-diaminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone.

[0154] Example 27

[0155] Preparation of compound VI:

[0156] When R3 = H:

[0157] In a reaction flask, ethanol (100 mL), 6-(3-nitro-4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (0.08 mol, 20 g), sulfuric acid aqueous solution (1 N, 60 mL), and 5% palladium on carbon (2 g) were added sequentially. The mixture was evacuated to purge nitrogen, followed by evacuation to purge hydrogen. The mixture was heated to 30–40 °C at a pressure of 0.2–0.4 bar. The reaction was monitored by TLC until complete. The mixture was cooled to room temperature, filtered, and the pH of the filtrate was adjusted to approximately 7 with sodium hydroxide aqueous solution. The ethanol was concentrated under reduced pressure, cooled to 0–10 °C, stirred for 1 h, filtered, and the filter cake was washed with water and dried to obtain 16.18 g of 6-(3,4-diaminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone.

[0158] Example 28

[0159] Preparation of compound VI:

[0160] When R3 = benzyl:

[0161] In a reaction flask, methanol (100 mL), 6-(3-nitro-4-benzylaminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (0.07 mol, 20 g), hydrochloric acid aqueous solution (1 N, 60 mL), and 5% palladium on carbon (1 g) were added sequentially. The mixture was evacuated to purge nitrogen, followed by evacuation to purge hydrogen. The mixture was heated to 30–40 °C at a pressure of 0.2–0.4 bar. The reaction was monitored by TLC until complete. The mixture was cooled to room temperature, filtered, and the pH of the filtrate was adjusted to approximately 7 with sodium hydroxide aqueous solution. The methanol was concentrated under reduced pressure, cooled to 0–10 °C, stirred for 1 h, filtered, and the filter cake was washed with water and dried to obtain 11.99 g of 6-(3,4-diaminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone.

[0162] Example 29

[0163] Preparation of compound VI:

[0164] When R3 = benzyl:

[0165] In a reaction flask, methanol (120 mL), 6-(3-nitro-4-benzylaminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (0.07 mol, 20 g), hydrochloric acid aqueous solution (1 N, 60 mL), and 5% palladium on carbon (0.6 g) were added sequentially. The mixture was evacuated to purge nitrogen, followed by evacuation to purge hydrogen. The mixture was heated to 50–60 °C at a pressure of 0.4–0.6 bar. The reaction was monitored by TLC until complete. The mixture was cooled to room temperature, filtered, and the pH of the filtrate was adjusted to approximately 7 with sodium hydroxide aqueous solution. The methanol was concentrated under reduced pressure, cooled to 0–10 °C, stirred for 1 h, filtered, and the filter cake was washed with water and dried to obtain 11.61 g of 6-(3,4-diaminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone.

[0166] Example 30

[0167] Preparation of compound VI:

[0168] When R3 = benzyl:

[0169] In a reaction flask, isopropanol (160 mL), 6-(3-nitro-4-benzylaminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (0.07 mol, 20 g), hydrochloric acid aqueous solution (1 N, 60 mL), and 5% palladium on carbon (2 g) were added sequentially. The mixture was evacuated to purge nitrogen, followed by evacuation to purge hydrogen. The mixture was heated to 40–50 °C at a pressure of 0.7–0.9 bar. The reaction was monitored by TLC until complete. The mixture was cooled to room temperature, filtered, and the pH of the filtrate was adjusted to approximately 7 with sodium hydroxide aqueous solution. The methanol was concentrated under reduced pressure, cooled to 0–10 °C, stirred for 1 h, filtered, and the filter cake was washed with water and dried to obtain 11.74 g of 6-(3,4-diaminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone.

[0170] Example 31

[0171] Preparation of compound VI:

[0172] When R3 = p-methyloxybenzyl:

[0173] In a reaction flask, methanol (120 mL), 6-(3-nitro-4-p-methoxybenzylaminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (0.05 mol, 20 g), hydrochloric acid aqueous solution (1 N, 60 mL), and 5% palladium on carbon (1 g) were added sequentially. The mixture was evacuated to purge nitrogen, followed by evacuation to purge hydrogen. The mixture was heated to 30–40 °C at a pressure of 0.2–0.4 bar. The reaction was monitored by TLC until complete. The mixture was cooled to room temperature, filtered, and the pH of the filtrate was adjusted to approximately 7 with sodium hydroxide aqueous solution. The methanol was concentrated under reduced pressure, cooled to 0–10 °C, stirred for 1 h, filtered, and the filter cake was washed with water and dried to obtain 10.9 g of 6-(3,4-diaminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone.

[0174] Example 32

[0175] Preparation of compound VI:

[0176] When R3 = p-methyloxybenzyl:

[0177] In a reaction flask, ethanol (160 mL), 6-(3-nitro-4-p-methoxybenzylaminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (0.05 mol, 20 g), hydrobromic acid aqueous solution (1 N, 60 mL), and 5% palladium on carbon (2 g) were added sequentially. The mixture was evacuated to purge nitrogen, followed by evacuation to purge hydrogen. The mixture was heated to 40–50 °C at a pressure of 0.5–0.7 bar. The reaction was monitored by TLC until complete. The mixture was cooled to room temperature, filtered, and the pH of the filtrate was adjusted to approximately 7 with sodium hydroxide aqueous solution. The methanol was concentrated under reduced pressure, cooled to 0–10 °C, stirred for 1 h, filtered, and the filter cake was washed with water and dried to obtain 10.78 g of 6-(3,4-diaminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone.

[0178] Example 33

[0179] Preparation of compound VI:

[0180] When R3 = p-methyloxybenzyl:

[0181] In a reaction flask, isopropanol (200 mL), 6-(3-nitro-4-p-methoxybenzylaminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (0.05 mol, 20 g), formic acid aqueous solution (1 N, 60 mL), and 10% palladium on carbon (0.4 g) were added sequentially. The mixture was evacuated to purge nitrogen, followed by evacuation to purge hydrogen. The mixture was heated to 50–60 °C at a pressure of 0.7–0.9 bar. The reaction was monitored by TLC until complete. The mixture was cooled to room temperature, filtered, and the pH of the filtrate was adjusted to approximately 7 with sodium hydroxide aqueous solution. The methanol was concentrated under reduced pressure, cooled to 0–10 °C, stirred for 1 h, filtered, and the filter cake was washed with water and dried to obtain 10.66 g of 6-(3,4-diaminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone.

[0182] Example 34

[0183] Preparation of pimoxane:

[0184] In a reaction flask, N,N-dimethylformamide (105 mL), 6-(3,4-diaminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (0.14 mol, 30 g), and sodium metabisulfite (0.15 mol, 28.74 g) were added sequentially. The mixture was heated to 110–115 °C, and p-methoxybenzaldehyde (0.14 mol, 18.71 g) was added dropwise. After the addition was complete, the mixture was reacted for another 1 h. The mixture was then cooled to 60–70 °C, filtered, and the filter cake was washed with DMF. The filtrate was cooled to 45–55 °C, and ammonia was added to adjust the pH to 8–9. The mixture was cooled to room temperature, and water (206 mL) was slowly added. The mixture was stirred for another 1–2 h, filtered, and the filter cake was rinsed with water, cooled to room temperature, and 400 mL of water was added. The mixture was then filtered, washed with water, and dried to obtain 41.9 g of pimoxendan.

[0185] Example 35

[0186] Preparation of pimoxane:

[0187] In a reaction flask, N,N-dimethylformamide (95 mL), 6-(3,4-diaminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (0.14 mol, 30 g), sodium metabisulfite (0.15 mol, 28.74 g), and p-methoxybenzaldehyde (0.14 mol, 18.71 g) were added sequentially. The mixture was heated to 120–130 °C and reacted for 1 h. After cooling to room temperature, water (475 mL) was slowly added, and the mixture was stirred for another 1–2 h. The mixture was filtered, and the filter cake was washed with water and dried to obtain 42.0 g of pimoxendan. MS (ESI): 335.32 [M+H] + . 1 HNMR (600M, DMSO, ppm): 12.91(s,1H,NH),10.97(s,1H,NH),8.15-8.16(d,2H,2×CH),7.97(s,1H,CH),7.60-7.72(m,2H,2×CH),7.12- 7.13(d,2H,2×CH),3.84(s,3H,CH3),3.48-3.50(m,1H,CH),2.71-2.75(dd,1H,CH2),2.25-2.28(d,1H,CH2),1.13-1.14(d,3H,CH3). 13 CNMR (600M, DMSO, ppm): 166.82, 161.27, 153.83, 153.13, 129.28, 128.64, 122.87, 120.51, 114.89, 55.80, 34.15, 27.94, 16.54.

[0188] In summary, the present invention has the following advantages:

[0189] (1) The nitration reaction step, which is highly dangerous and generates a large amount of waste acid water, has been eliminated;

[0190] (2) This route has a short procedure, and pimoxand can be obtained in six steps;

[0191] (3) All raw and auxiliary materials used in this route are industrially available and readily purchased products;

[0192] (4) This route is simple to operate and does not require column chromatography purification.

[0193] The above description is only a preferred embodiment of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the inventive concept of the present invention, and these should also be considered within the scope of protection of the invention.

Claims

1. A method for synthesizing pimoxendan, comprising: Step 1: Friedel-Crafts acylation reaction; Step 2: Substitution and hydrolysis reaction; Step 3: Decarboxylation and ring closure reaction; Step 4: Substitution reaction; Step 5: Reduction reaction; Step 6: Ring closure reaction; Characterized by: Step 1, Friedel-Crafts acylation reaction: Compound I and compound A undergo a Friedel-Crafts acylation reaction in an aprotic solvent under the action of a Lewis acid to generate compound II; Step 2, Substitution and Hydrolysis Reaction: Using ether as a solvent, under alkaline conditions, compound II undergoes a substitution reaction with dimethyl malonate or diethyl malonate. The resulting compound undergoes a hydrolysis reaction in an alkaline aqueous solution to generate compound III. Step 3, decarboxylation and ring-closure reaction: Compound III is heated under the conditions of hydrazine hydrate and acid to generate compound IV; Step 4, Substitution Reaction: Compound IV undergoes a substitution reaction with an amine in a polar solvent to produce compound V; Step 5, Reduction reaction: Compound V reacts in an acidic aqueous solution of a protic solvent under the conditions of palladium on carbon and hydrogen to produce compound VI; The reaction equation is as follows: Wherein: R is F, Cl, Br or a lower alkoxy group, and the lower alkoxy group is an alkoxy group with ≤3 carbon atoms; R1 is Cl or Br; R2 is methyl or ethyl; R3 is H, benzyl or p-methoxybenzyl; The acids in step three are formic acid, acetic acid, and propionic acid; the reaction temperature is 60–115℃; the molar ratio of compound III to hydrazine hydrate is 1:2–5.

2. The method for synthesizing pimoxendan according to claim 1, characterized in that, In step one, the Lewis acid is aluminum trichloride, ferric trichloride, or zinc chloride; the aprotic solvent is dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, or carbon disulfide; when R1 is Cl, the reaction temperature is 30–80℃; when R1 is Br, the reaction temperature is -20–30℃; the molar ratio of compound I: compound A: Lewis acid is 1:1.05–1.3:1.5–3.

3. The method for synthesizing pimoxendan according to claim 1, characterized in that, The ether in step two is: diethyl ether, tetrahydrofuran, methyl tert-butyl ether, dioxane, ethylene glycol dimethyl ether, or ethylene glycol diethyl ether; the base in the alkaline conditions is: sodium hydroxide, sodium methoxide, or sodium ethoxide; the base in the alkaline aqueous solution is: lithium hydroxide, sodium hydroxide, or potassium hydroxide; the reaction temperature is -20 to 30°C; the molar ratio of compound II: dimethyl malonate or ethyl malonate: base: base in the alkaline aqueous solution is 1:1.2 to 2.5:1.5 to 3:3 to 5.

4. The method for synthesizing pimoxendan according to claim 1, characterized in that, The solvent used in step four is N,N-dimethylformamide, N,N-dimethylacetamide, or n-butanol.

5. The method for synthesizing pimoxendan according to claim 1, characterized in that, The reaction temperature in step four is 90–110°C.

6. The method for synthesizing pimoxendan according to claim 1, characterized in that, In step four, when R3 = H, NH3 is in large excess, and the pressure inside the reactor is 0.2 to 10 Bar; when R3 is benzyl or methoxybenzyl, the molar ratio of compound IV to NH2R3 is 1:3 to 8.

7. The method for synthesizing pimoxendan according to claim 1, characterized in that, The solvent used in step five is methanol, ethanol, propanol or isopropanol; the acid in the acidic aqueous solution is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, formic acid or acetic acid.

8. The method for synthesizing pimoxendan according to claim 1, characterized in that, The solvent used in step five is methanol; the acid in the acidic aqueous solution is selected from hydrochloric acid.

9. The method for synthesizing pimoxendan according to claim 1, characterized in that, The reaction temperature in step five is 30–60°C; the hydrogen pressure is controlled at 0.2–0.9 Bar.

10. The method for synthesizing pimoxendan according to claim 1, characterized in that, In step five, the weight ratio of compound V to palladium on carbon is 1:0.01 to 0.1.

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