Pimobendan intermediate and synthesis method thereof

Abstract

The present invention discloses a pimobendan intermediate synthesis method, which comprises: 1, carrying out a Friedel-Crafts acylation reaction on a compound I and a compound A in an aprotic solvent under the effect of a Lewis acid to generate a compound II; 2, ether is used as a solvent, under the alkaline condition, the compound II and dimethyl malonate or diethyl malonate are subjected to a substitution reaction, the generated compound is subjected to a hydrolysis reaction in an aqueous alkali solution, and a compound III is generated; and 3, heating the compound III under the conditions of hydrazine hydrate and acid to generate a compound IV, namely the pimobendan intermediate. The synthesis method cancels a nitration reaction step which is high in risk and generates a large amount of waste acid water, and is short in route 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 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 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 drug is the first calcium sensitizer 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 attention, and the preparation of the corresponding essential key intermediate pyridazinone compounds has also become a focus of attention. For the preparation of such intermediates, the starting materials of the routes currently on the market are chlorobenzene, 4-chlorobenzaldehyde or acetanilide, and these routes all require nitration reactions, which are dangerous and easily produce a large amount of strong acid wastewater, and 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 intermediates.

[0005] Patent US4361563A proposes to use chlorobenzene as the starting material to obtain a pyridazinone intermediate through nine steps, which involves a dangerous nitration reaction, uses bromine which is highly toxic, and has 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" proposed using 4-chlorobenzaldehyde as the starting material to obtain an intermediate (one of Compounds IV) through four 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" proposed a six-step synthesis of pyridazinone intermediates using acetylaniline as the starting material. 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" proposed a seven-step method to prepare a pyridazinone intermediate 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 to use acetanilide as the starting material and obtain a pyridazinone intermediate through four 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 large-scale production (Scheme 5).

[0018] Scheme 5:

[0019]

[0020] Patents CN107522663A and CN111518081A propose to use acetanilide as a starting material to prepare a pyridazinone intermediate through six 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 routes for synthesizing pimobendan pyridazinone intermediates 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, developing a synthetic route for pimobendan intermediates suitable for industrial scale-up production is particularly important for the industrialization of pimobendan drugs. 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 prior art problems.

[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 ≤ 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 Lewis acid to generate compound II;

[0030] Step 2: Using ether as 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., pimobendan intermediate;

[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 one, in step one, 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, 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: hydrazine hydrate is 1:2-5.

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

[0044] (1) The nitration step, which is highly 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 is 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 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.

[0053] Example 2

[0054] Preparation of compound II:

[0055] When R1=Cl:

[0056] 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.

[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 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 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.

[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, 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.

[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 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.

[0073] Example 7

[0074] Preparation of compound III:

[0075] When R2=Me:

[0076] 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.

[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 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.

[0081] Example 9

[0082] Preparation of compound III:

[0083] When R2=Me:

[0084] 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.

[0085] Example 10

[0086] Preparation of compound III:

[0087] When R2=Et:

[0088] 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.

[0089] Embodiment 11

[0090] Preparation of compound III:

[0091] When R2=Et:

[0092] 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.

[0093] Example 12

[0094] Preparation of compound III:

[0095] When R2=Et:

[0096] 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.

[0097] Example 13

[0098] Preparation of compound IV:

[0099] 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, and filter 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] Embodiment 14

[0101] Preparation of compound IV:

[0102] 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, and filter 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] Embodiment 15

[0104] Preparation of compound IV:

[0105] 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 under ice bath for 1 h, and filter 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, 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, 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 step, which is highly 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, 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 pimobendan intermediate, characterized in that: The structural formula of the intermediate is: Wherein: R is a lower alkoxy group, and a lower alkoxy group is an alkoxy group with a carbon number of ≤3, excluding methoxy.

2. 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 Lewis acid to generate compound II; Step 2: Using ether as 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., pimobendan intermediate; 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.

3. A method for synthesizing a pimobendan intermediate according to claim 2, characterized in that, 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.

4. A method for synthesizing a pimobendan intermediate according to claim 2, 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.

5. A method for synthesizing a pimobendan intermediate according to claim 2, characterized in that, In step 1, the molar ratio of compound I: compound A: Lewis acid is 1: 1.05-1.3: 1.5-3.

6. A method for synthesizing a pimobendan intermediate according to claim 2, 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 or sodium ethoxide; the base in the alkaline aqueous solution includes but is not limited to lithium hydroxide, sodium hydroxide or potassium hydroxide.

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

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

9. A method for synthesizing a pimobendan intermediate according to claim 2, characterized in that: The acid in step three includes but is not limited to formic acid, acetic acid or propionic acid; the reaction temperature in step three is 60-115°C.

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

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