A kind of pimobendan intermediate and its synthesis method

Abstract

The invention discloses a method for synthesizing a pimobendan intermediate, comprising the following steps: Step 1: 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: Using ether as a solvent and under alkaline conditions, Compound II undergoes a substitution reaction with dimethyl malonate or diethyl malonate, and the resulting compound undergoes a hydrolysis reaction in an alkaline aqueous solution to generate Compound III; Step 3: Compound III is heated under the conditions of hydrazine hydrate and an acid to generate Compound IV, i.e., the pimobendan intermediate. This synthetic method eliminates the nitration reaction step, which is highly dangerous and produces a large amount of waste acid water, and has a short route and simple operation.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical organic chemical synthesis, in particular to a pimobendan intermediate and a synthesis method thereof. 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 clinically used to treat 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 its enhanced cardiac contractile protein response to Ca. 2+ It has a strong sensitivity to calcium and an inhibitory effect on phosphodiesterase III (PDEIII), making it the first calcium sensitizer drug to be marketed. The chemical name of this product is: 4,5-dihydro-6-[2-(4-methoxyphenyl)-1H-benzimidazol-5-yl]-5-methyl-3(2H)-pyridazinone, and it has the following chemical structure:

[0003]

[0004] Since pimobendan was launched in Japan, its preparation method has become a focus of public attention, and the preparation of the corresponding key intermediate pyridazinone compounds has also attracted attention. For the preparation of such intermediates, the starting materials of the routes currently available on the market include chlorobenzene, 4-chlorobenzaldehyde, or acetanilide. These routes all require nitration reactions, which are dangerous and easily produce large amounts 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, all of which are disadvantageous factors for the production of pimobendan intermediates.

[0005] Patent US4361563A proposes a nine-step process using chlorobenzene as a starting material to obtain a pyridazinone intermediate, which involves a dangerous nitration reaction and the use of highly toxic bromine, and the process is relatively lengthy (Scheme 1).

[0006] Scheme 1:

[0007]

[0008] The document "R Jonas, M Klockow, I Lues. Eur. J. Med. Chem. 1993, 28, 129" proposes a four-step process using 4-chlorobenzaldehyde as the starting material to obtain an intermediate (one of Compounds IV), involving the highly toxic substance potassium cyanide and a nitration reaction. This route is highly dangerous for industrial production and produces a large amount of waste acid (Scheme 2).

[0009] Scheme 2:

[0010]

[0011] The literature "Park Ri-yang et al. Chinese Journal of Medicinal Chemistry, 1994, 4(1), 41" proposed a six-step synthesis of pyridazinone intermediates using acetylaniline as the starting material. This route also used the highly toxic potassium cyanide and carried out 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" proposed a seven-step process for preparing pyridazinone intermediates using acetanilide as the starting material. This route uses a dangerous nitration reaction and toxic bromine, and the steps are relatively long, and each step requires column purification (Scheme 4).

[0015] Scheme 4:

[0016]

[0017] Patent CN106518850A proposes a four-step process using acetanilide as a starting material to produce a pyridazinone intermediate. This route not only involves a nitration reaction, but also uses the starting material, 2-methyl-3-methoxycarbonylpropionyl chloride, which is a non-chemical product and difficult to obtain in large quantities on the market, hindering scale-up production (Scheme 5).

[0018] Scheme 5:

[0019]

[0020] Patents CN107522663A and CN111518081A propose a six-step process for preparing pyridazinone intermediates using acetanilide as a starting material. This route not only involves 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 for pimobendan pyridazinone intermediates utilize bromine and potassium cyanide, both of which are highly toxic and have limited industrial use, or difficult-to-find starting materials. Furthermore, all involve nitration reactions, which are highly dangerous and generate a large amount of waste acid water. These routes are not suitable for industrial scale-up production. Therefore, developing a synthetic route for pimobendan pyridazinone intermediates suitable for industrial scale-up production is particularly important for the industrialization of pimobendan. Summary of the Invention

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

[0025] On the one hand, the present invention provides a pimobendan intermediate, the structural formula of the intermediate is:

[0026]

[0027] Wherein: R is a lower alkoxy group, and the lower alkoxy group is an alkoxy group with a carbon number of ≤3.

[0028] On the other hand, the present invention provides a method for synthesizing a pimobendan intermediate, comprising the following steps:

[0029] Step 1: Compound I and compound A undergo Friedel-Crafts acylation reaction in an aprotic solvent under the action of a Lewis acid to produce compound II;

[0030] Step 2: Using ether as a solvent, under alkaline conditions, compound II undergoes a substitution reaction with dimethyl malonate or diethyl malonate, and the resulting compound undergoes a hydrolysis reaction in an alkaline aqueous solution to produce compound III;

[0031] Step 3: Compound III is heated under the conditions of hydrazine hydrate and acid to generate compound IV, i.e., the intermediate of pimobendan;

[0032] The reaction equation is as follows:

[0033]

[0034] Wherein: R is F, Cl, Br, I or lower alkoxy, lower alkoxy is alkoxy with carbon number ≤ 3; R1 is Cl or Br; R2 is Me or Et.

[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.

[0036] In certain embodiments, in step 1, when R1 is Cl, the reaction temperature is 30 to 80°C; when R1 is Br, the reaction temperature is -20 to 30°C.

[0037] In certain embodiments, in step 1, the molar ratio of compound I: compound A: Lewis acid is 1:1.05-1.3:1.5-3.

[0038] 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 phosphate, 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.

[0039] In certain embodiments, the reaction temperature in step 2 is -20 to 30°C.

[0040] In certain embodiments, in step 2, the molar ratio of compound II: dimethyl or ethyl malonate: base: base water is 1:1.2-2.5:1.5-3:3-5.

[0041] In certain embodiments, the acid in step three includes but is not limited to formic acid, acetic acid or propionic acid; and the reaction temperature in step three is 60-115°C.

[0042] In certain embodiments, in step three, the molar ratio of compound III to hydrazine hydrate is 1:2-5.

[0043] Compared with the prior art, the present invention has the following beneficial effects:

[0044] (1) The nitration reaction step, which is dangerous and produces a large amount of waste acid water, is eliminated;

[0045] (2) This route is short and can obtain the key pyridazinone intermediate of pimobendan in three steps;

[0046] (3) All raw materials and auxiliary materials used in this route are industrially available and readily available products;

[0047] (4) This route is simple to operate and does not require column chromatography purification. DETAILED DESCRIPTION

[0048] The present invention will be further described in detail below through embodiments.

[0049] Example 1

[0050] Preparation of compound II:

[0051] When R1=Cl:

[0052] 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 liquid was separated, and 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 62.98 g of 2-chloro-1-(4-chloro-3-nitrophenyl)-propan-1-one.

[0053] Example 2

[0054] Preparation of compound II:

[0055] When R1=Cl:

[0056] 1,2-Dichloroethane (500 mL), o-fluoronitrobenzene (0.35 mol, 50 g), and 2-chloropropionyl chloride (0.41 mol, 51.74 g) were added to the reaction flask in sequence, and 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 cooled to room temperature and poured into 500 mL of stirred ice water. The liquid was separated, and 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 66.47 g of 2-chloro-1-(4-fluoro-3-nitrophenyl)-propan-1-one.

[0057] Example 3

[0058] Preparation of compound II:

[0059] When R1=Cl:

[0060] 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 liquid was separated, and 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.

[0061] Example 4

[0062] Preparation of compound II:

[0063] When R1=Br:

[0064] 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 mixture was slowly restored to room temperature for reaction. The reaction was completed after 1 h, and the mixture was poured into 500 mL of stirred ice water. The liquid was separated, and 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 70.89 g of 2-bromo-1-(4-bromo-3-nitrophenyl)-propan-1-one.

[0065] Example 5

[0066] Preparation of compound II:

[0067] When R1=Br:

[0068] 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, and zinc chloride (0.41 mol, 56.42 g) was added in batches. After the addition, the mixture was slowly restored to room temperature for reaction. The reaction was completed after 3 h, and the mixture was poured into 500 mL of stirred ice water. The liquid was separated, and 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 52.35 g of 2-bromo-1-(4-isopropoxy-3-nitrophenyl)-propan-1-one.

[0069] Example 6

[0070] Preparation of compound II:

[0071] When R1=Br:

[0072] 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 mixture 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 liquid was separated, and 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 47.03 g of 2-bromo-1-(4-methoxy-3-nitrophenyl)-propan-1-one.

[0073] Example 7

[0074] Preparation of compound III:

[0075] When R2=Me:

[0076] Tetrahydrofuran (320 mL) and sodium hydride (0.24 mol, 8.47 g) were added to the reaction flask in sequence, stirred evenly, cooled to -20°C, and dimethyl malonate (0.19 mol, 25.56 g) was added dropwise. After the addition, the mixture was reacted at no higher than 10°C for 30 minutes. 2-Chloro-1-(4-chloro-3-nitrophenyl)-propan-1-one (0.16 mol, 40 g) was added and the mixture was reacted at no higher than 30°C for 5 to 6 hours. After the reaction was complete, 250 g of an aqueous solution of sodium hydroxide (0.81 mol, 32.25 g) was added dropwise and the mixture was reacted at no higher than 30°C until the reaction was complete as detected by TLC. The mixture was cooled to -10°C, and ice water (100 mL) and methyl tert-butyl ether (300 mL) were added with stirring. The mixture was separated, and the pH value of the aqueous phase was adjusted to ≈1 with concentrated hydrochloric acid under ice bath, and the mixture was extracted with ethyl acetate (300 mL × 3). The organic phase was washed with saturated aqueous sodium chloride 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.

[0077] Example 8

[0078] Preparation of compound III:

[0079] When R2=Me:

[0080] Add methyl tert-butyl ether (320 mL) and sodium methoxide (0.44 mol, 23.86 g) to the reaction flask in sequence, stir evenly, cool to -20°C, add dimethyl malonate (0.29 mol, 38.9 g) dropwise, and 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) and react at no higher than 30°C for 5 to 6 hours. When the reaction is complete, 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 liquid 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.

[0081] Example 9

[0082] Preparation of compound III:

[0083] When R2=Me:

[0084] Ethylene glycol dimethyl ether (320 mL) and sodium ethoxide (0.29 mol, 23.86 g) were added to the reaction flask in sequence, stirred evenly, cooled to -20°C, and dimethyl malonate (0.29 mol, 39.21 g) was added dropwise. After the addition, the mixture was reacted at no higher than 10°C for 30 minutes. 2-Bromo-1-(4-bromo-3-nitrophenyl)-propan-1-one (0.12 mol, 40 g) was added and the mixture was reacted at no higher than 30°C for 5 to 6 hours. When the reaction was complete, 250 g of an aqueous solution of lithium hydroxide (0.47 mol, 11.37 g) was added dropwise and the mixture was reacted at no higher than 30°C until the reaction was 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 with stirring, and the liquid 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 42.32 g of (2-carboxy-3-(3-nitro-4-bromobenzoyl)-butyric acid.

[0085] Example 10

[0086] Preparation of compound III:

[0087] When R2=Et:

[0088] Add diethyl ether (320 mL) and sodium methoxide (0.36 mol, 19.57 g) to the reaction flask in sequence, stir evenly, cool to -20°C, add diethyl malonate (0.17 mol, 27.85 g) dropwise, and react at no higher than 10°C for 30 minutes. Then add 2-bromo-1-(4-fluoro-3-nitrophenyl)-propan-1-one (0.14 mol, 40 g) and react at no higher than 30°C for 5 to 6 hours. When the reaction is complete, add 250 g of lithium hydroxide (0.43 mol, 10.41 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, the liquid was separated, the aqueous phase was adjusted to pH ≈1 with concentrated hydrochloric acid under ice bath, extracted with ethyl acetate (300 mL × 3), the organic phase was washed with saturated brine (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.

[0089] Example 11

[0090] Preparation of compound III:

[0091] When R2=Et:

[0092] Tetrahydrofuran (320 mL) and sodium ethoxide (0.28 mol, 18.9 g) were added to the reaction flask in sequence, stirred evenly, cooled to -20°C, and diethyl malonate (0.21 mol, 34.22 g) was added dropwise. After the addition, the mixture was reacted at no higher than 10°C for 30 minutes. 2-Bromo-1-(4-methoxy-3-nitrophenyl)-propan-1-one (0.14 mol, 40 g) was added and the mixture was reacted at no higher than 30°C for 5 to 6 hours. After the reaction was complete, 250 g of an aqueous solution of sodium hydroxide (0.47 mol, 18.99 g) was added dropwise and the mixture was reacted at no higher than 30°C until the reaction was complete as detected by TLC. The mixture was cooled to -10°C, and ice water (100 mL) and methyl tert-butyl ether (300 mL) were added with stirring. The mixture was separated, and the pH value of the aqueous phase was adjusted to ≈1 with concentrated hydrochloric acid under an ice bath, and the mixture was 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 41.49 g of (2-carboxy-3-(3-nitro-4-methoxybenzoyl)-butyric acid.

[0093] Example 12

[0094] Preparation of compound III:

[0095] When R2=Et:

[0096] Ethylene glycol dimethyl ether (320 mL) and sodium hydride (0.47 mol, 18.63 g) were added to the reaction flask in sequence, stirred evenly, cooled to -20°C, and diethyl malonate (0.39 mol, 62.16 g) was added dropwise. After the addition, the mixture was reacted at no higher than 10°C for 30 minutes. 2-chloro-1-(4-ethoxy-3-nitrophenyl)-propan-1-one (0.16 mol, 40 g) was added and the mixture was reacted at no higher than 30°C for 5 to 6 hours. When the reaction was complete, 250 g of potassium hydroxide (0.78 mol, 56.11 g) aqueous solution was added dropwise and the mixture was reacted at no higher than 30°C until the reaction was complete as detected by TLC. The mixture was cooled to -10°C, and ice water (100 mL) and methyl tert-butyl ether (300 mL) were added with stirring. The mixture was separated, and the pH value of the aqueous phase was adjusted to ≈1 with concentrated hydrochloric acid under ice bath, and the mixture was extracted with ethyl acetate (300 mL × 3). The organic phase was washed with saturated aqueous sodium chloride 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.

[0097] Example 13

[0098] Preparation of compound IV:

[0099] To a reaction flask, 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) were added sequentially. The mixture was heated to 60-70°C and reacted for 24 h. The mixture was cooled to room temperature and slowly poured into ice water (200 mL). The mixture was stirred in an ice bath for 1 h and filtered 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] + .

[0100] Example 14

[0101] Preparation of compound IV:

[0102] To a reaction flask, 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) were added sequentially. The mixture was heated to 80-90°C and reacted for 16 h. The mixture was cooled to room temperature and slowly poured into ice water (240 mL). The mixture was stirred in an ice bath for 1 h and filtered 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] + .

[0103] Example 15

[0104] Preparation of compound IV:

[0105] 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) were added to the reaction flask in sequence. The mixture was heated to 90-100°C and reacted for 12 h. The mixture was cooled to room temperature and slowly poured into ice water (240 mL). The mixture was stirred in an ice bath for 1 h and filtered 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] + .

[0106] Example 16

[0107] Preparation of compound IV:

[0108] 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. The mixture was heated to 100-115°C and reacted for 8 h. The mixture was cooled to room temperature and slowly poured into ice water (200 mL). The mixture was stirred in an ice bath for 1 h and filtered 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] + .

[0109] 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] + .

[0110] The preparation method of 6-(3-nitro-4-iodophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone is the same as above. MS (ESI): 360.1 [M+H] +

[0111] 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] + .

[0112] 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] + .

[0113] In summary, the present invention has the following advantages:

[0114] (1) The nitration reaction step, which is dangerous and produces a large amount of waste acid water, is eliminated;

[0115] (2) This route is short and can obtain the key pyridazinone intermediate of pimobendan in three steps;

[0116] (3) All raw materials and auxiliary materials used in this route are industrially available and readily available products;

[0117] (4) This route is simple to operate and does not require column chromatography purification.

[0118] The above description is only a preferred embodiment of the present invention. It should be pointed out that a person skilled in the art can make several 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 a pimobendan intermediate, characterized in that: The following steps are involved: Step 1: Compound I and compound A undergo Friedel-Crafts acylation reaction in an aprotic solvent under the action of a Lewis acid to produce compound II; Step 2: Using ether as a solvent, under alkaline conditions, compound II undergoes a substitution reaction with dimethyl malonate or diethyl malonate, and the resulting compound undergoes a hydrolysis reaction in an alkaline aqueous solution to produce compound III; Step 3: Compound III is heated under the conditions of hydrazine hydrate and acid to generate compound IV, i.e., the intermediate of pimobendan; The reaction equation is as follows: Wherein: R is F, Cl, Br, I or lower alkoxy, lower alkoxy is alkoxy with carbon number ≤ 3; R1 is Cl or Br; R2 is Me or Et; The acid in step 3 is formic acid, acetic acid or propionic acid; the reaction temperature in step 3 is 60-115°C.

2. The synthetic method of a pimobendan intermediate according to claim 1, wherein The Lewis acid in step 1 is aluminum chloride, ferric chloride or zinc chloride; the aprotic solvent is dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride or carbon disulfide.

3. A method for synthesizing a pimobendan intermediate according to claim 1, characterized in that, In step 1, when R1 is Cl, the reaction temperature is 30 to 80°C; when R1 is Br, the reaction temperature is -20 to 30°C.

4. The synthetic method of a pimobendan intermediate according to claim 1, wherein In step 1, the molar ratio of compound I: compound A: Lewis acid is 1:1.05-1.3:1.5-3.

5. A method for synthesizing a pimobendan intermediate according to claim 1, characterized in that, The ether in step 2 is: diethyl ether, tetrahydrofuran, methyl tert-butyl ether, dioxane, ethylene glycol dimethyl ether or ethylene glycol diethyl ether; the base in the alkaline condition is: sodium hydrogen phosphate, sodium methoxide or sodium ethoxide; the base in the alkaline aqueous solution is lithium hydroxide, sodium hydroxide or potassium hydroxide.

6. A method for synthesizing a pimobendan intermediate according to claim 1, characterized in that, The reaction temperature in step 2 is -20 to 30°C.

7. A method for synthesizing a pimobendan intermediate according to claim 1, characterized in that, In step 2, the molar ratio of compound II: dimethyl malonate or ethyl malonate: base: base in the aqueous base solution is 1:1.2-2.5:1.5-3:3-5.

8. A method for synthesizing a pimobendan intermediate according to claim 1, characterized in that, In step 3, the molar ratio of compound III to hydrazine hydrate is 1:2-5.

Images