Synthesis method of pimobendan

Abstract

The invention discloses a synthesis method of pimobendan, which comprises the following steps: Friedel-Crafts acylation reaction: carrying out Friedel-Crafts acylation reaction on a compound I and a compound A in an aprotic solvent under the action of Lewis acid to generate a compound II; substitution and hydrolysis reaction: ether is used as a solvent, under the alkaline condition, the compound II and dimethyl malonate or diethyl malonate are subjected to substitution reaction, the generated compound is subjected to hydrolysis reaction in aqueous alkali, and a compound III is generated; decarboxylation ring closing reaction: heating the compound III under the conditions of hydrazine hydrate and acid to generate a compound IV; substitution reaction: carrying out substitution reaction on the compound IV and amine in a polar solvent to generate a compound V; reduction reaction: reacting the compound V in an acidic aqueous solution of a protonic solvent under the conditions of palladium carbon and hydrogen to generate a compound VI; and carrying out ring closing reaction to obtain the pimobendan. The method is high in safety, short in circuit step and simple to operate.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical organic chemical synthesis, and in particular to a synthesis method of pimobendan. Background Art

[0002] Pimobendan (UD-CG115BS, Acardi, CAS: 74150-27-9) is a vasodilator-like cardiotonic drug developed by Boehringer Ingelheim in Germany and first marketed in Japan in 1994. It is a phosphodiesterase inhibitor and is mainly used in the treatment of heart failure. The mechanism of action of this drug is different from that of traditional cardiotonic drugs. Its positive inotropic effect is mainly attributed to the enhancement of myocardial contractile protein to Ca 2+ 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 structure:

[0003]

[0004] Since Pimobendan was launched in Japan, its preparation method has also become a focus of attention. For the preparation of Pimobendan, the starting materials of the routes currently on the market are chlorobenzene, 4-chlorobenzaldehyde or acetanilide, and these routes all require nitration reaction, which is dangerous and easily produces a large amount of strong acid wastewater. In addition, the routes are relatively long, or some reactions require the use of highly toxic potassium cyanide or highly toxic bromine, or some reactions require column chromatography purification, which are all unfavorable factors for the production of Pimobendan.

[0005] The original patent US4361563A reported that chlorobenzene was used as the starting material and pimobendan was prepared through eleven steps, which involved a dangerous nitration reaction, used bromine with high toxicity, and had a relatively long process (Scheme 1).

[0006] Scheme 1:

[0007]

[0008] The document "R Jonas, M Klockow, I Lues. Eur. J. Med. Chem. 1993, 28, 129" reported that 4-chlorobenzaldehyde was used as the starting material and pimobendan was obtained through seven steps, in which highly toxic potassium cyanide was used and a nitration reaction was performed. This route is too dangerous for industrial production and will produce a lot of waste acid water (Scheme 2).

[0009] Scheme 2:

[0010]

[0011] The document "Piao Riyang et al. Chinese Journal of Medicinal Chemistry, 1994, 4(1), 41" reported the synthesis of pyridazinone intermediates using acetylaniline as the starting material through six steps. This route also used highly toxic potassium cyanide and carried out a nitration reaction (Scheme 3).

[0012] Scheme 3:

[0013]

[0014] The document "Wang Sisi, Shen Jiacong. Chinese Journal of Medicinal Chemistry, 1997, 7(3), 185" reported that pimobendan was prepared in seven steps using acetanilide as the starting material. This route used a dangerous nitration reaction and bromine, which is highly toxic. The steps were relatively long and each step required column purification (Scheme 4).

[0015] Scheme 4:

[0016]

[0017] Patent CN106518850A reports that acetanilide is used as the starting material to obtain pimobendan through six steps. This route not only uses a nitration reaction, but also the starting material 2-methyl-3-methoxycarbonyl propionyl chloride used is a non-chemical product, which is difficult to buy in large quantities on the market, and is not conducive to amplification production (Scheme 5).

[0018] Scheme 5:

[0019]

[0020] Patents CN107522663A and CN111518081A propose to use acetanilide as a starting material and prepare pimobendan in seven steps. This route not only uses a nitration reaction, but also has a relatively long number of steps (Scheme 6).

[0021] Scheme 6:

[0022]

[0023] In summary, the publicly reported synthetic routes of pimobendan use bromine and potassium cyanide, which are highly toxic and limited in industrial use, or starting materials that are difficult to buy, and all involve nitration reactions that are highly dangerous and produce a lot of waste acid water. These routes are not suitable for industrial scale-up production. Therefore, it is particularly important to develop a synthetic route of pimobendan suitable for industrial scale-up production for the industrialization of pimobendan drugs. Summary of the invention

[0024] The object of the present invention is to provide a method for synthesizing pimobendan, so as to solve one or more of the above-mentioned problems in the prior art.

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

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

[0027] Step 2, substitution and hydrolysis reaction: using ether as solvent, under alkaline conditions, compound II undergoes substitution reaction with dimethyl malonate or diethyl malonate, and the resulting compound undergoes hydrolysis reaction in alkaline aqueous solution to generate compound III;

[0028] Step 3, decarboxylation ring-closing 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 substitution reaction with amine in a polar solvent to generate compound V;

[0030] Step 5, reduction reaction: Compound V is reacted in an acidic aqueous solution of a protic solvent under the conditions of palladium carbon and hydrogen to generate compound VI;

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

[0032] The reaction equation is as follows:

[0033]

[0034] Wherein: R is F, Cl, Br or a lower alkoxy group, and a lower alkoxy group is an alkoxy group with a carbon number of ≤3; R 1 is Cl or Br; R 2 is methyl or ethyl; R 3 is H, benzyl or p-methoxybenzyl.

[0035] In certain embodiments, the Lewis acid in step 1 includes but is not limited to the following compounds: aluminum chloride, ferric chloride 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 R 1 When it is Cl, the reaction temperature is 30~80℃; when R 1 When it is Br, the reaction temperature is -20 to 30°C; the molar ratio of compound I: compound A: Lewis acid is 1:1.05 to 1.3:1.5 to 3.

[0036] In certain embodiments, the ether in step 2 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 condition includes but is not limited to: sodium hydrogen, sodium methoxide, 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 water base is 1:1.2 to 2.5:1.5 to 3:3 to 5.

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

[0038] In certain embodiments, the solvent used in step 4 is N,N-dimethylformamide, N,N-dimethylacetamide or n-butanol.

[0039] In certain embodiments, the reaction temperature in step 4 is 90-110°C.

[0040] In certain embodiments, in step 4, when R 3 =H, NH 3 Large excess, the pressure in the kettle is 0.2~10Bar; when R 3 When it is benzyl or methoxybenzyl, compound IV: NH 2 R 3 The molar ratio is 1:3~8.

[0041] In certain 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 certain embodiments, the reaction temperature in step five is 30-60° C.; the hydrogen pressure is controlled to be 0.2-0.9 Bar.

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

[0044] Step 6: Compound VI and p-methoxybenzaldehyde undergo ring-closing reaction. For the specific synthesis method, refer to patent WO2011124638A.

[0045] Compared with the prior art, the present invention has the following beneficial effects:

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

[0047] (2) This route is short and can obtain pimobendan in six steps;

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

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

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

[0051] Example 1

[0052] Preparation of compound II:

[0053] When R 1 =Cl:

[0054] Dichloromethane (500 mL), o-chloronitrobenzene (0.32 mol, 50 g), and 2-chloropropionyl chloride (0.33 mol, 42.31 g) were added to the reaction flask in sequence, and 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 cooled to room temperature and poured into 500 mL of stirred ice water. The organic phase was washed with water (150 mL), an ice saturated aqueous sodium bicarbonate solution (150 mL), and an aqueous solution (150 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained solid was crystallized with a mixed solution of ethyl acetate and petroleum ether to obtain 62.98 g of 2-chloro-1-(4-chloro-3-nitrophenyl)-propan-1-one.

[0055] Example 2

[0056] Preparation of compound II:

[0057] When R 1 =Cl:

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

[0059] Example 3

[0060] Preparation of compound II:

[0061] When R 1 =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 to the reaction flask in sequence, and aluminum chloride (0.6 mol, 80.00 g) was added at room temperature. The mixture was heated to reflux and reacted for 3 h until the reaction was complete. The mixture was cooled to room temperature and poured into 500 mL of stirred ice water. The organic phase was washed with water (150 mL), an ice saturated aqueous sodium bicarbonate solution (150 mL), and an aqueous solution (150 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained 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)-propan-1-one.

[0063] Example 4

[0064] Preparation of compound II:

[0065] When R 1 =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 to the reaction flask in sequence, cooled to -20°C, and aluminum chloride (0.74 mol, 99.01 g) was added in batches. After the addition, the temperature was slowly restored to room temperature for reaction. The reaction was completed after 1 hour, and the mixture was poured into 500 mL of stirred ice water. The organic phase was separated and washed with water (150 mL), saturated sodium bicarbonate aqueous solution (150 mL) and aqueous solution (150 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained solid was crystallized from a mixed solution of ethyl acetate and petroleum ether to obtain 70.89 g of 2-bromo-1-(4-bromo-3-nitrophenyl)-propan-1-one.

[0067] Example 5

[0068] Preparation of compound II:

[0069] When R 1 =Br:

[0070] Chloroform (500 mL), 4-isopropoxynitrobenzene (0.28 mol, 50 g) and 2-bromopropionyl bromide (0.33 mol, 71.48 g) were added to the reaction flask in sequence, cooled to -10°C, zinc chloride (0.41 mol, 56.42 g) was added in batches, and the temperature was slowly restored to room temperature after the addition. The reaction was completed after 3 h, and the mixture was poured into 500 mL of stirred ice water, separated, and the organic phase was washed with water (150 mL), ice saturated sodium bicarbonate aqueous solution (150 mL), and aqueous solution (150 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained solid was crystallized from a mixed solution of ethyl acetate and petroleum ether to obtain 52.35 g of 2-bromo-1-(4-isopropoxy-3-nitrophenyl)-propan-1-one.

[0071] Example 6

[0072] Preparation of compound II:

[0073] When R 1 =Br:

[0074] Dichloromethane (500 mL), 4-methoxynitrobenzene (0.33 mol, 50 g), and 2-bromopropionyl bromide (0.36 mol, 77.53 g) were added to the reaction flask in sequence, cooled to -15°C, and ferric chloride (0.65 mol, 105.92 g) was added in batches. After the addition, the temperature was slowly restored to room temperature for reaction. The reaction was completed after 1 hour, and the mixture was poured into 500 mL of stirred ice water. The liquids were separated, and the organic phase was washed with water (150 mL), icy saturated sodium bicarbonate aqueous solution (150 mL), and aqueous solution (150 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained solid was crystallized from a mixed solution of ethyl acetate and petroleum ether to obtain 47.03 g of 2-bromo-1-(4-methoxy-3-nitrophenyl)-propan-1-one.

[0075] Example 7

[0076] Preparation of compound III:

[0077] When R 2 =Me:

[0078] Add tetrahydrofuran (320 mL) and sodium hydride (0.24 mol, 8.47 g) to the reaction bottle in sequence, stir evenly, cool to -20°C, add dimethyl malonate (0.19 mol, 25.56 g) dropwise, react at no higher than 10°C for 30 minutes after addition, then add 2-chloro-1-(4-chloro-3-nitrophenyl)-propan-1-one (0.16 mol, 40 g), react at no higher than 30°C for 5 to 6 hours, and when the reaction is complete, add 250 g of sodium hydroxide (0.81 mol, 32.25 g) aqueous solution dropwise, and react at no higher than 30°C until the reaction is complete as detected by TLC. The mixture was cooled to -10°C, ice water (100 mL) and methyl tert-butyl ether (300 mL) were added, stirred, and separated. The aqueous phase was adjusted to pH ≈ 1 with concentrated hydrochloric acid under ice bath, extracted with ethyl acetate (300 mL × 3), and the organic phase was washed with saturated saline solution (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 50.39 g of (2-carboxy-3-(3-nitro-4-chlorobenzoyl)-butyric acid.

[0079] Example 8

[0080] Preparation of compound III:

[0081] When R 2 =Me:

[0082] Add methyl tert-butyl ether (320 mL) and sodium methoxide (0.44 mol, 23.86 g) to the reaction bottle in sequence, stir evenly, cool to -20°C, add dimethyl malonate (0.29 mol, 38.9 g) dropwise, react at no higher than 10°C for 30 minutes after addition, then add 2-chloro-1-(4-isopropoxy-3-nitrophenyl)-propan-1-one (0.15 mol, 40 g), react at no higher than 30°C for 5 to 6 hours, and react completely. Add 250 g of potassium hydroxide (0.44 mol, 24.78 g) aqueous solution dropwise, and react at no higher than 30°C until the reaction is complete as detected by TLC. The mixture was cooled to -10°C, ice water (100 mL) was added and stirred, and the mixture was separated. The aqueous phase was adjusted to pH ≈ 1 with concentrated hydrochloric acid under ice bath, and extracted with ethyl acetate (300 mL × 3). The organic phase was washed with saturated saline solution (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 48.45 g of (2-carboxy-3-(3-nitro-4-isopropoxybenzoyl)-butyric acid.

[0083] Example 9

[0084] Preparation of compound III:

[0085] When R 2 =Me:

[0086] Add ethylene glycol dimethyl ether (320 mL) and sodium ethoxide (0.29 mol, 23.86 g) to the reaction bottle in sequence, stir evenly, cool to -20°C, add dimethyl malonate (0.29 mol, 39.21 g) dropwise, react at no higher than 10°C for 30 minutes after addition, then add 2-bromo-1-(4-bromo-3-nitrophenyl)-propan-1-one (0.12 mol, 40 g), react at no higher than 30°C for 5 to 6 hours, and when the reaction is complete, add 250 g of lithium hydroxide (0.47 mol, 11.37 g) aqueous solution dropwise, and react at no higher than 30°C until the reaction is complete as detected by TLC. The mixture was cooled to -10°C, ice water (100 mL) and methyl tert-butyl ether (300 mL) were added, stirred, and separated. The aqueous phase was adjusted to pH ≈ 1 with concentrated hydrochloric acid under ice bath, extracted with ethyl acetate (300 mL × 3), and the organic phase was washed with saturated saline solution (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 42.32 g of (2-carboxy-3-(3-nitro-4-bromobenzoyl)-butyric acid.

[0087] Example 10

[0088] Preparation of compound III:

[0089] When R 2 =Et:

[0090] Add ether (320mL) and sodium methoxide (0.36mol, 19.57g) to the reaction bottle in sequence, stir evenly, cool to -20℃, add diethyl malonate (0.17mol, 27.85g) dropwise, react at no higher than 10℃ for 30 minutes after addition, then add 2-bromo-1-(4-fluoro-3-nitrophenyl)-propan-1-one (0.14mol, 40g), react at no higher than 30℃ for 5-6h, and react completely, add 250g of lithium hydroxide (0.43mol, 10.41g) aqueous solution dropwise, and react at no higher than 30℃ until the reaction is complete as detected by TLC. The mixture was cooled to -10°C, ice water (100 mL) was added and stirred, and the mixture was separated. The aqueous phase was adjusted to pH ≈ 1 with concentrated hydrochloric acid under ice bath, and extracted with ethyl acetate (300 mL × 3). The organic phase was washed with saturated saline solution (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 42.92 g of (2-carboxy-3-(3-nitro-4-fluorobenzoyl)-butyric acid.

[0091] Embodiment 11

[0092] Preparation of compound III:

[0093] When R 2 =Et:

[0094] Add tetrahydrofuran (320 mL) and sodium ethoxide (0.28 mol, 18.9 g) to the reaction bottle in sequence, stir evenly, cool to -20°C, add diethyl malonate (0.21 mol, 34.22 g) dropwise, react at no higher than 10°C for 30 minutes after addition, then add 2-bromo-1-(4-methoxy-3-nitrophenyl)-propan-1-one (0.14 mol, 40 g), react at no higher than 30°C for 5 to 6 hours, and when the reaction is complete, add 250 g of sodium hydroxide (0.47 mol, 18.99 g) aqueous solution dropwise, and react at no higher than 30°C until the reaction is complete as detected by TLC. The mixture was cooled to -10°C, ice water (100 mL) and methyl tert-butyl ether (300 mL) were added, stirred, and separated. The aqueous phase was adjusted to pH ≈ 1 with concentrated hydrochloric acid under ice bath, extracted with ethyl acetate (300 mL × 3), and the organic phase was washed with saturated saline solution (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 41.49 g of (2-carboxy-3-(3-nitro-4-methoxybenzoyl)-butyric acid.

[0095] Example 12

[0096] Preparation of compound III:

[0097] When R 2 =Et:

[0098] Add ethylene glycol dimethyl ether (320 mL) and sodium hydride (0.47 mol, 18.63 g) to the reaction bottle in sequence, stir evenly, cool to -20°C, add diethyl malonate (0.39 mol, 62.16 g) dropwise, react at no higher than 10°C for 30 minutes after addition, then add 2-chloro-1-(4-ethoxy-3-nitrophenyl)-propan-1-one (0.16 mol, 40 g), react at no higher than 30°C for 5 to 6 hours, and when the reaction is complete, add 250 g of potassium hydroxide (0.78 mol, 56.11 g) aqueous solution dropwise, and react at no higher than 30°C until the reaction is complete as detected by TLC. The mixture was cooled to -10°C, ice water (100 mL) and methyl tert-butyl ether (300 mL) were added, stirred, and separated. The aqueous phase was adjusted to pH ≈ 1 with concentrated hydrochloric acid under ice bath, extracted with ethyl acetate (300 mL × 3), and the organic phase was washed with saturated saline solution (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 48.48 g of (2-carboxy-3-(3-nitro-4-ethoxybenzoyl)-butyric acid.

[0099] Embodiment 13

[0100] Preparation of compound IV:

[0101] Add formic acid (120 mL), (2-carboxy-3-(3-nitro-4-fluorobenzoyl)-butyric acid (0.13 mol, 40 g), and 80% hydrazine hydrate (0.27 mol, 16.73 g) to the reaction bottle in sequence, heat to 60-70°C, react for 24 hours, cool to room temperature, slowly pour in ice water (200 mL), stir in an ice bath for 1 hour, filter and dry 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] Embodiment 14

[0103] Preparation of compound IV:

[0104] Add formic acid (160 mL), (2-carboxy-3-(3-nitro-4-chlorobenzoyl)-butyric acid (0.13 mol, 40 g), and 80% hydrazine hydrate (0.51 mol, 31.72 g) to the reaction bottle in sequence, heat to 80-90°C, react for 16 h, cool to room temperature, slowly pour in ice water (240 mL), stir in an ice bath for 1 h, filter and dry 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] Embodiment 15

[0106] Preparation of compound IV:

[0107] Add acetic acid (160 mL), (2-carboxy-3-(3-nitro-4-methoxybenzoyl)-butyric acid (0.13 mol, 40 g), and 80% hydrazine hydrate (0.39 mol, 24.13 g) to the reaction bottle in sequence, heat to 90-100°C, react for 12 h, cool to room temperature, slowly pour in ice water (240 mL), stir in an ice bath for 1 h, filter and dry 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), (2-carboxy-3-(3-nitro-4-ethoxybenzoyl)-butyric acid (0.12 mol, 40 g), and 80% hydrazine hydrate (0.61 mol, 38.48 g) were added to the reaction flask in sequence, heated to 100-115°C, reacted for 8 h, cooled to room temperature, slowly poured into ice water (200 mL), stirred in an ice bath for 1 h, 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 of 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 of 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 of 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] Embodiment 17

[0115] Preparation of Compound V:

[0116] When R 3 =H:

[0117] In a reaction kettle, 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 in sequence. Under stirring, vacuum was evacuated, ammonia was introduced, and the mixture was heated to 90-100° C. and the pressure was 0.2-0.4 bar. The reaction was carried out for 24 hours. The reaction was complete when detected by TLC. The mixture was cooled to room temperature, 600 mL of water was added, the mixture was stirred and filtered, and the mixture was 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] Embodiment 18

[0119] Preparation of Compound V:

[0120] When R 3 =H:

[0121] In a reaction kettle, 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 in sequence. Under stirring, vacuum was evacuated, ammonia was introduced, and the mixture was heated to 100-110° C. and the pressure was 0.8-1 bar. The reaction was carried out for 24 hours. The reaction was complete when detected by TLC. The mixture was cooled to room temperature, 600 mL of water was added, the mixture was stirred and filtered, and the mixture was 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] Embodiment 19

[0123] Preparation of Compound V:

[0124] When R 3 =H:

[0125] In a reaction kettle, 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 in sequence. Under stirring, vacuum was evacuated, ammonia was introduced, and the mixture was heated to 100-110° C. and the pressure was 1-2 bar. The reaction was carried out for 12 h. The reaction was complete when detected by TLC. The mixture was cooled to room temperature, 600 mL of water was added, the mixture was stirred and filtered, and the mixture was 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] Embodiment 20

[0127] Preparation of Compound V:

[0128] When R 3 =H:

[0129] In a reaction kettle, 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 in sequence. Under stirring, vacuum was evacuated, ammonia was introduced, and the mixture was heated to 90-100° C. and the pressure was 8-10 bar. The reaction was carried out for 10 h. The reaction was completed when detected by TLC. The mixture was cooled to room temperature, 600 mL of water was added, and the mixture was stirred and filtered. The mixture was 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] Embodiment 21

[0131] Preparation of Compound V:

[0132] When R 3 =benzyl, p-methoxybenzyl:

[0133] In a reaction flask, add 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) in sequence, heat to 90-100°C, react for 12 h, and detect the completion of the reaction by TLC. Cool to room temperature, add 180 mL of water, filter, wash with water, and dry to obtain 26.15 g of 6-(3-nitro-4-p-methoxybenzylaminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone.

[0134] Embodiment 22

[0135] Preparation of Compound V:

[0136] When R 3 =benzyl, p-methoxybenzyl:

[0137] In a reaction bottle, add 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) in sequence, heat to 100-110°C, react for 12 h, and detect the completion of the reaction by TLC. Cool to room temperature, add 240 mL of water, filter, wash with water, and dry to obtain 20.81 g of 6-(3-nitro-4-benzylaminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone.

[0138] Embodiment 23

[0139] Preparation of Compound V:

[0140] When R 3 =benzyl, p-methoxybenzyl:

[0141] In a reaction flask, add 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) in sequence, heat to 90-100°C, react for 10 h, and detect the completion of the reaction by TLC. Cool to room temperature, add 400 mL of water, filter, wash with water, and dry to obtain 24.42 g of 6-(3-nitro-4-benzylaminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone.

[0142] Embodiment 24

[0143] Preparation of Compound V:

[0144] When R 3 =benzyl, p-methoxybenzyl:

[0145] In a reaction flask, add 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) in sequence, heat to 100°C~110°C, react for 10 h, and the reaction is complete when detected by TLC. Cool to room temperature, add 400 mL of water, filter, wash with water, and dry to obtain 24.28 g of 6-(3-nitro-4-p-methoxybenzylaminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone.

[0146] Embodiment 25

[0147] Preparation of compound VI:

[0148] When R 3 =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 (1N, 60 mL), 10% palladium carbon (0.2 g) were added in sequence, and the nitrogen was replaced by vacuum, and then the hydrogen was replaced by vacuum. The reaction was heated to 50-60°C and the pressure was 0.7-0.9 bar. The reaction was completed by TLC detection. The temperature was lowered to room temperature and filtered. The filtrate was adjusted to pH ≈ 7 with sodium hydroxide aqueous solution. Methanol was concentrated under reduced pressure, the temperature was lowered to 0-10°C, stirred for 1 h, filtered, 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] Embodiment 26

[0151] Preparation of compound VI:

[0152] When R 3 =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), aqueous hydrochloric acid solution (1N, 60 mL), and 5% palladium carbon (1 g) were added in sequence, and the nitrogen was replaced by vacuum, and then the hydrogen was replaced by vacuum. The reaction was heated to 40-50° C. and the pressure was 0.5-0.7 bar. The reaction was completed by TLC detection. The temperature was lowered to room temperature and filtered. The filtrate was adjusted to pH ≈ 7 with aqueous sodium hydroxide solution. Methanol was concentrated under reduced pressure, the temperature was lowered to 0-10° C., stirred for 1 h, filtered, 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] Embodiment 27

[0155] Preparation of compound VI:

[0156] When R 3 =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), aqueous sulfuric acid solution (1N, 60 mL), and 5% palladium carbon (2 g) were added in sequence, and the nitrogen was replaced by vacuum, and then the hydrogen was replaced by vacuum. The reaction was heated to 30-40° C. and the pressure was 0.2-0.4 bar. The reaction was completed by TLC detection. The temperature was lowered to room temperature and filtered. The filtrate was adjusted to pH ≈ 7 with aqueous sodium hydroxide solution. The ethanol was concentrated under reduced pressure, the temperature was lowered to 0-10° C., stirred for 1 h, filtered, 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] Embodiment 28

[0159] Preparation of compound VI:

[0160] When R 3 =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), aqueous hydrochloric acid solution (1N, 60 mL), and 5% palladium carbon (1 g) were added in sequence, and the nitrogen was replaced by vacuum, and then the hydrogen was replaced by vacuum. The reaction was heated to 30-40°C and the pressure was 0.2-0.4 bar. The reaction was completed by TLC detection. The temperature was lowered to room temperature and filtered. The filtrate was adjusted to pH ≈ 7 with aqueous sodium hydroxide solution. Methanol was concentrated under reduced pressure, the temperature was lowered to 0-10°C, stirred for 1 h, filtered, 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] Embodiment 29

[0163] Preparation of compound VI:

[0164] When R 3 =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), aqueous hydrochloric acid solution (1N, 60 mL), and 5% palladium carbon (0.6 g) were added in sequence, and the nitrogen was replaced by vacuum, and then the hydrogen was replaced by vacuum. The reaction was heated to 50-60°C and the pressure was 0.4-0.6 bar. The reaction was completed by TLC detection. The temperature was lowered to room temperature and filtered. The filtrate was adjusted to pH ≈ 7 with aqueous sodium hydroxide solution. The methanol was concentrated under reduced pressure, the temperature was lowered to 0-10°C, stirred for 1 h, filtered, 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] Embodiment 30

[0167] Preparation of compound VI:

[0168] When R 3 =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), aqueous hydrochloric acid solution (1N, 60 mL), and 5% palladium carbon (2 g) were added in sequence, and the nitrogen was replaced by vacuum, and then the hydrogen was replaced by vacuum. The reaction was heated to 40-50° C. and the pressure was 0.7-0.9 bar. The reaction was completed by TLC detection. The temperature was lowered to room temperature and filtered. The filtrate was adjusted to pH ≈ 7 with aqueous sodium hydroxide solution. 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] Embodiment 31

[0171] Preparation of compound VI:

[0172] When R 3 =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), aqueous hydrochloric acid solution (1N, 60 mL), and 5% palladium carbon (1 g) were added in sequence, and the nitrogen was replaced by vacuum, and then the hydrogen was replaced by vacuum. The mixture was heated to 30-40°C and the pressure was 0.2-0.4 bar. The reaction was completed by TLC detection. The mixture was cooled to room temperature and filtered. The filtrate was adjusted to pH ≈ 7 with aqueous sodium hydroxide solution. 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] Embodiment 32

[0175] Preparation of compound VI:

[0176] When R 3 =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 (1N, 60 mL), 5% palladium carbon (2 g) were added in sequence, and the nitrogen was replaced by vacuum, and then the hydrogen was replaced by vacuum. The mixture was heated to 40-50° C. and the pressure was 0.5-0.7 bar. The reaction was completed by TLC detection. The mixture was cooled to room temperature and filtered. The filtrate was adjusted to pH ≈ 7 with sodium hydroxide aqueous solution. 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] Embodiment 33

[0179] Preparation of compound VI:

[0180] When R 3 =p-methyloxybenzyl:

[0181] In a reaction flask, add 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 (1N, 60 mL), 10% palladium carbon (0.4 g) in sequence, evacuate to replace nitrogen, then evacuate to replace hydrogen, heat to 50-60°C, pressure at 0.7-0.9 bar, TLC detection reaction is complete, cool to room temperature, filter, the filtrate is adjusted to pH ≈ 7 with sodium hydroxide aqueous solution, methanol is concentrated under reduced pressure, cooled to 0-10°C, stirred for 1 h, filtered, the filter cake is washed with water, and dried to obtain 10.66 g of 6-(3,4-diaminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone.

[0182] Embodiment 34

[0183] Preparation of Pimobendan:

[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), sodium metabisulfite (0.15 mol, 28.74 g) were added in sequence, heated to 110-115°C, p-anisaldehyde (0.14 mol, 18.71 g) was added dropwise, and the addition was completed. The mixture was reacted for another 1 h, cooled to 60-70°C, filtered, and the filter cake was washed with DMF. The filtrate was cooled to 45-55°C, ammonia water was added to adjust the pH to 8-9, cooled to room temperature, water (206 mL) was slowly added, and stirred for another 1-2 h. The mixture was filtered, the filter cake was rinsed with water, cooled to room temperature, 400 mL of water was added, filtered, washed with water, and dried to obtain 41.9 g of pimobendan.

[0185] Embodiment 35

[0186] Preparation of Pimobendan:

[0187] In the reaction bottle, N, N-dimethylformamide (95mL), 6-(3,4-diaminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (0.14mol, 30g), sodium metabisulfite (0.15mol, 28.74g), p-anisaldehyde (0.14mol, 18.71g) were added in sequence, heated to 120-130°C, reacted for 1h, cooled to room temperature, slowly added water (475mL), stirred for 1-2h, filtered, the filter cake was washed with water and dried to obtain 42.0g of pimobendan. MS (ESI): 335.32 [M+H] + . 1HNMR (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,CH 3 ),3.48-3.50(m,1H,CH),2.71-2.75(dd,1H,CH 2 ),2.25-2.28(d,1H,CH 2 ),1.13-1.14(d,3H,CH 3 ). 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 step, which is highly dangerous and produces a large amount of waste acid water, is eliminated;

[0190] (2) This route is short and can obtain pimobendan in six steps;

[0191] (3) All raw materials and auxiliary materials used in this route are industrially available and readily available 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 pointed out that, for ordinary technicians in this field, several modifications and improvements can be made without departing from the creative concept of the present invention, and these should also be regarded as within the scope of protection of the invention.

Claims

1. A synthetic method for pimobendan, comprising: Step 1: Friedel-Crafts acylation reaction; Step 2: substitution and hydrolysis reaction; Step 3: decarboxylation ring-closing reaction; Step 4: substitution reaction; Step 5: reduction reaction; Step 6: ring-closing reaction; characterized in that: Step 1, Friedel-Crafts acylation reaction: Compound I and compound A undergo Friedel-Crafts acylation reaction in an aprotic solvent under the action of Lewis acid to generate compound II; Step 2, substitution and hydrolysis reaction: using ether as solvent, under alkaline conditions, compound II undergoes substitution reaction with dimethyl malonate or diethyl malonate, and the resulting compound undergoes hydrolysis reaction in alkaline aqueous solution to generate compound III; Step 3, decarboxylation ring-closing reaction: Compound III is heated under the conditions of hydrazine hydrate and acid to generate compound IV; Step 4, substitution reaction: Compound IV undergoes substitution reaction with amine in a polar solvent to generate compound V; Step 5, reduction reaction: Compound V is reacted in an acidic aqueous solution of a protic solvent under the conditions of palladium carbon and hydrogen to generate compound VI; The reaction equation is as follows: Wherein: R is F, Cl, Br or lower alkoxy, lower alkoxy is alkoxy with carbon number ≤ 3; R1 is Cl or Br; R2 is methyl or ethyl; R3 is H, benzyl or p-methoxybenzyl.

2. A synthetic method for pimobendan according to claim 1, characterized in that, In step 1, the Lewis acid includes but is not limited to the following compounds: aluminum chloride, ferric chloride 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 to 80°C; when R1 is Br, the reaction temperature is -20 to 30°C; the molar ratio of compound I: compound A: Lewis acid is 1:1.05 to 1.3:1.5 to 3.

3. A synthetic method for pimobendan according to claim 1, characterized in that, The ether in step 2 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 condition includes but is not limited to: sodium hydrogen, sodium methoxide, 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 ester: base: alkaline water is 1:1.2 to 2.5:1.5 to 3:3 to 5.

4. A method for synthesizing pimobendan according to claim 1, characterized in that, The acid in step three includes but is not limited to: formic acid, acetic acid, propionic acid; the reaction temperature is 60-115° C.; the molar ratio of compound III: hydrazine hydrate is 1:2-5.

5. A synthetic method for pimobendan according to claim 1, characterized in that, The solvent used in step 4 is N,N-dimethylformamide, N,N-dimethylacetamide or n-butanol.

6. A method for synthesizing pimobendan according to claim 1, characterized in that, The reaction temperature of step 4 is 90-110°C.

7. A method for synthesizing pimobendan according to claim 1, characterized in that, In step 4, when R3=H, NH3 is in large excess and the pressure in the autoclave is 0.2-10 Bar; when R3 is benzyl or methoxybenzyl, the molar ratio of compound IV: NH2R3 is 1:3-8.

8. A method for synthesizing pimobendan according to claim 1, characterized in that, 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.

9. A method for synthesizing pimobendan according to claim 1, characterized in that, Step 5: The reaction temperature is 30-60°C; the hydrogen pressure is controlled to be 0.2-0.9 Bar.

10. A method for synthesizing pimobendan according to claim 1, characterized in that, In step 5, the weight ratio of compound V to palladium carbon (5% or 10%) is 1:0.01-0.1.

Images